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Item 1. Business

2022-02-24 compared with 2021-02-25 · 116 added, 139 removed, 220 unchanged (54% of the section changed)

We are a clinical-stage, biotechnology company, developing new treatment options for cancer patients in indications with the greatest medical need, including KRAS-mutated metastatic colorectal cancer (“mCRC”), pancreatic cancer, metastatic castrate-resistant prostate cancer (“mCRPC”) and leukemias.

By integrating biomarkers into our clinical development programs, we will be able to identify patients who are most likely to respond to treatment across a number of cancer types and associated indications.

Our drug candidate, onvansertib, is a first-in-class, third-generation, oral and highly selective Polo-like Kinase 1 (“PLK1”) adenosine triphosphate (“ATP”) competitive inhibitor.

PLK1 is essential for precisely regulating the cell division and maintaining genome stability in mitosis (cell division), spindle assembly, and DNA damage response.

Studies have shown that PLK1 is over-expressed in most cancers, which is associated with poor prognosis in patients.

Data has shown that blocking the expression of PLK1 by kinase inhibitors can effectively inhibit proliferation and induce apoptosis (death) of tumor cells.

On March 15, 2017, we announced the licensing of onvansertib from Nerviano Medical Sciences S.r.l.

(“Nerviano”), the largest company in Italy committed to innovation and research and development in oncology and a leader in protein kinase drug development (Polo-like Kinase Inhibitors).

We believe onvansertib is the only PLK1 selective ATP competitive inhibitor administered orally with apparent antitumor activity in different preclinical models currently in clinical development.

PLK1 is the most well-characterized member of the family of serine/threonine protein kinases and strongly promotes the progression of cells through mitosis.

PLK1 performs several important functions throughout the mitotic (M) phase of the cell cycle, including the regulation of centrosome maturation and spindle assembly, the removal of cohesins from chromosome arms, the inactivation of anaphase-promoting complex/cyclosome inhibitors, and the regulation of mitotic exit and cytokinesis.

PLK1 is ubiquitously expressed in normal proliferating tissues and is over-expressed in a wide variety of human tumors (including lung, colon, prostate, ovary, breast, and head and neck squamous cell carcinoma).

Onvansertib was developed to have high selectivity for PLK1, to be administered orally, and to have a relatively short drug half-life of approximately 24 hours compared to previous pan Polo-like inhibitors.

Onvansertib has been tested in-vivo in different xenograft and transgenic models at times suggesting tumor growth inhibition or tumor regression.

Onvansertib has been tested for antiproliferative activity on a panel of 148 tumor cell lines and appeared highly active with an IC 50 (a measure concentration for 50% target inhibition) below 100 nM in 75 cell lines and IC 50 values below 1 uM in 133 out of 148 cell lines.

A Phase 1 safety study was successfully completed in patients with advanced metastatic solid tumors and published in 2017 in Investigational New Drugs .

We have four active Investigational New Drug (“IND”) applications in place with the U.S.

Food and Drug Administration (“FDA”), and three ongoing clinical studies.

The first study is TROV-052 (ClinicalTrials.gov Identifier NCT03303339), a Phase 1b/2 open-label clinical trial of onvansertib in combination with standard-of-care low-dose cytarabine (“LDAC”) or decitabine for patients with relapsed or refractory AML.

The second study is TROV-053 (ClinicalTrials.gov Identifier NCT03414034), a Phase 2 open-label clinical trial of onvansertib in combination with Zytiga ® (abiraterone acetate)/prednisone, all administered orally, for patients with metastatic Castration-Resistant Prostate Cancer (“mCRPC”).

The third study is TROV-054 (ClincalTrials.gov Identifier NCT03829410), a Phase 1b/2 open-label clinical trial of onvansertib in combination with FOLFIRI (folinic acid, fluorouracil and irinotecan) and Avastin ® (bevacizumab) for patients with mCRC, who have a KRAS mutation.

A new Phase 2 trial of onvansertib in combination with nanoliposomal irinotecan, leucovorin and fluorouracil for the second-line treatment of patients with metastatic pancreatic ductal adenocarcinoma (PDAC) is planned for initiation in the first half of 2021 (ClinicalTrials.gov Identifier NCT04752696)

Development of onvansertib, as part of a combination regimen with already approved drugs, has the potential to bring new treatment options to patients across a wide array of cancers.

Onvansertib has been evaluated preclinically in combination with several different chemotherapies, including irinotecan, cisplatin, cytarabine, doxorubicin, gemcitabine and paclitaxel, and with targeted therapeutics such as abiraterone, histone deacetylase (HDAC) inhibitors, fms-like tyrosine kinase 3 (FLT3) inhibitors, and bortezomib.

These therapies are used clinically for the treatment of many hematologic and solid cancers, including acute myeloid leukemia (AML), non-Hodgkin’s lymphoma (NHL), metastatic CRC, metastatic castration resistant prostate cancer (mCRPC), adrenocortical carcinoma (ACC), triple negative breast cancer (TNBC), small cell lung cancer (SCLC), and ovarian cancer.

Our strategy includes integrating a predictive clinical biomarker approach into our onvansertib clinical development programs, which we believe may enable us to tailor treatment to specific sub-populations of patients who are most likely to respond and have a positive clinical impact.

Onvansertib Phase 1 Safety Study in Solid Tumors

A Phase 1 safety study of onvansertib was completed in patients with advanced metastatic solid tumor cancers and published in July 2017, in the peer-reviewed journal Investigational New Drugs .

Glen Weiss, Medical Oncologist at Goodyear, AZ and affiliated with Cancer Treatment Centers of America at Western Regional Medical Center, was the principal investigator and first author of the publication, entitled “Phase 1 Dose-Escalation Study of NMS-1286937, an Orally Available Polo-like Kinase 1 Inhibitor, in Patients with Advanced or Metastatic Solid Tumors” This study evaluated first-cycle dose limiting toxicities and related maximum tolerated dose with data indicating a manageable safety profile for onvansertib (also known as PCM-075 and NMS-1286937) for the treatment of advanced or metastatic solid tumors, with transient adverse events that were likely related to the drug’s mechanism of action.

The authors believe that data from preclinical work, coupled with the results of the Phase 1 trial, suggest that onvansertib could become a new therapeutic option for the treatment of solid tumor and hematologic cancers.

In this trial, onvansertib was administered orally, once daily for five consecutive days, every three weeks, to evaluate first cycle dose-limiting toxicities and related maximum tolerated dose in adult subjects with advanced/metastatic solid tumors.

The study was also intended to evaluate onvansertib’s pharmacokinetic profile in plasma, its anti-tumor activity, and its ability to modulate intracellular targets in biopsied tissue.

The study identified thrombocytopenia and neutropenia as the primary toxicities, which is consistent with the expected mechanism of action of onvansertib and results from preclinical studies.

These hematologic toxicities were reversible, with recovery usually occurring within 3 weeks.

No GI disorders, mucositis, or alopecia was observed, confirming that bone marrow cells are the most sensitive to onvansertib inhibition with the applied dosing schedule.

We are utilizing the existing IND applications to develop onvansertib in solid tumors as part of our clinical development expansion plans, with our initial focus in mCRC and mCRPC.

Onvansertib Phase 2 Study in metastatic Castration-Resistant Prostate Cancer

On December 14, 2017, we announced the submission of our Phase 2 protocol of onvansertib in combination with abiraterone acetate (Zytiga ® - Johnson & Johnson) for the treatment of mCRPC, to the FDA and our active solid tumor IND.

In this multi-center, open-label, Phase 2 trial, onvansertib in combination with the standard dose of Zytiga ® and prednisone, all administered orally, will be evaluated for safety and efficacy.

The primary efficacy endpoint is the proportion of patients achieving disease control after 12 weeks of study treatment, as defined by lack of Prostate Specific Antigen (“PSA”) progression in patients who are showing signs of early progressive disease (rise in PSA but minimally symptomatic or asymptomatic) while currently receiving androgen deprivation therapy (“ADT”), abiraterone and prednisone.

This ongoing Phase 2 clinical study is being conducted at three Harvard Medical sites:

Beth Israel Deaconess Medical Center, Dana Farber Cancer Institute and Massachusetts General Hospital, in Boston Massachusetts.

David Einstein at the Genitourinary Oncology Program at Beth Israel Deaconess Medical Center and Harvard Medical School is the principal investigator for the Phase 2 mCRPC trial.

Onvansertib Phase 1b/2 Study in metastatic Colorectal Cancer

In December 2018, we submitted a new IND application and protocol for our Phase 1b/2 trial of onvansertib in combination with FOLFIRI and Avastin ® (bevacizumab) for the second-line treatment of mCRC with a KRAS mutation.

On January 16, 2019, we received notification from the FDA that the “ study may proceed ” and on January 29, 2019, we announced an agreement with PoC Capital, LLC to fund the clinical development program.

In this open-label, Phase 1b/2 trial, onvansertib in combination with standard-of-care FOLFIRI and Avastin ® is being evaluated for safety and efficacy.

The trial will enroll up to 44 patients to assess the safety and preliminary efficacy of the combination regimen.

The Phase1b segment of this clinical study has been conducted at two prestigious cancer centers:

USC Norris Comprehensive Cancer Center and The Mayo Clinic Arizona.

Heinz-Josef Lenz, Associate Director for Clinical Research and Co-Leader of the Gastrointestinal Cancers Program at the USC Norris Comprehensive Cancer Center, is the principal investigator for the Phase 1b/2 mCRC trial.

The Phase 2 segment is being conducted at USC Norris Comprehensive Cancer Center, the Mayo Clinic (Arizona, Minnesota and Florida), Kansas University Medical Center and CARTI Cancer Research.

Onvansertib Phase 1b/2 Study in Acute Myeloid Leukemia

In June 2017, we announced the submission of our IND application and our Phase 1b/2 protocol of onvansertib in combination with standard-of-care chemotherapy for the treatment of AML to the FDA.

In July 2017, we received notification from the FDA that our Phase 1b/2 clinical trial of onvansertib in patients with AML “may proceed”.

On October 9, 2017, we announced that the FDA granted Orphan Drug Designation to onvansertib for the treatment of AML.

We initiated our Phase 1b/2 AML trial in November 2017 and enrolled our first patient in February 2018.

On August 29, 2018, we announced that the European Medicinal Agency granted Orphan Drug Designation to onvansertib for the treatment of AML in the European Union (“EU”).

The Phase 1b/2 clinical study is an open-label trial to evaluate the safety and anti-leukemic activity of onvansertib in combination with standard-of-care chemotherapy in patients with AML.

Phase 1b is a dose escalation trial to evaluate the safety, tolerability, dose and scheduling of onvansertib, and to determine a recommended clinical treatment dose for the Phase 2 continuation trial.

Enrollment of Phase 2 was completed in 2020.

Pharmacokinetics of onvansertib and correlative biomarker activity have been assessed throughout the Phase 1b and Phase 2 segments of the trial.

The Phase 2 continuation trial is open-label with administration of the recommended onvansertib clinical dose in combination with standard-of-care chemotherapy to further evaluate safety and assess efficacy.

In 2019, we completed the Phase 1b segment of this trial and enrollment in Phase 2 was completed in October 2020.

A total of eight sites are conducting this trial, which is being led by Hematologist Amer Zeidan, MBBS, MHS, Assistant Professor of Medicine at Yale School of Medicine, Hematology expert at Yale Cancer Center.

We are a clinical-stage oncology company, developing new precision medicine treatment options for cancer patients in indications with the greatest unmet medical need.

Our goal is to target tumor vulnerabilities with treatment combinations that overcome disease resistance and improve disease response to standard treatment regimens and to increase overall survival.

We are developing onvansertib, an oral and highly-selective Polo-like Kinase 1 ("PLK1") inhibitor, in combination with standard-of-care anti-cancer therapeutics.

Our clinical development programs incorporate tumor genomics and biomarker assays to refine assessment of patient response to treatment.

Our Drug Candidate, Onvansertib

Onvansertib, our lead compound, is a novel, highly potent, highly selective PLK1 inhibitor.

PLK1, a serine/threonine kinase, has a well-understood mechanism of action within tumor cell proliferation and is overexpressed in a number of tumors (including colorectal, pancreatic, prostate, ovarian, breast and lung cancer).

In particular, PLK1’s activity in various phases of the cell cycle provide multiple targets for a PLK1 inhibitor to inhibit DNA repair and interrupt cell division, thereby killing tumor cells.

PLK1 inhibition has been considered an attractive target of anti-tumor therapeutics for the last two decades, however past PLK1 drug candidates have failed to show acceptable tolerability and efficacy.

We believe the attributes of onvansertib described below, as well as clinical evidence of favorable safety and efficacy, with expected on-target, easy to manage and reversible side effects, may prove beneficial in addressing clinical therapeutic needs across a variety of cancers:

• Onvansertib is highly potent and highly selective against the PLK1 enzyme (IC 50 = 2nM;

IC 50 is the concentration for 50% inhibition), compared to prior PLK1 inhibitors that were pan-inhibitors of several PLK targets.

Low or no activity of onvansertib was observed on a panel of 63 kinases (IC50>500 nM), including the PLK members PLK2 and PLK3 (IC 50 >10,000 nM).

• Onvansertib has a relatively short drug half-life of 24 hours, compared to a half-life of approximately 5 days for prior PLK1 inhibitors.

A short half-life allows for flexible dosing and improved managing of drug concentrations to reduce dose-related toxicities.

• Onvansertib is orally bioavailable, compared to prior PLK1 inhibitors that were delivered intravenously, allowing for relative ease of dosing.

In vitro studies have shown synergistic effects when onvansertib was administered in combination with different cytotoxic agents including antimicrotubule agents, topoisomerase 1 inhibitors, antimetabolites, alkylating agents, proteasome inhibitors, kinase inhibitors, BCL-2 inhibitors, and androgen biosynthesis inhibitors.

In addition, in vivo combination studies have confirmed the positive results obtained in vitro and synergistic effects have been observed in xenograft models of onvansertib in combination with irinotecan (including NKTR-102), 5-fluorouracil ("5-FU"), abiraterone, quizartinib, venetoclax, and paclitaxel, while additive effects in combination with cytarabine or bevacizumab have been demonstrated.

There are three ongoing clinical trials in onvansertib in combination treatment:

second line treatment in patients with KRAS-mutated Metastatic Colorectal Cancer ("mCRC"), second line treatment in patients with Metastatic Pancreatic Ductal Adenocarcinoma ("mPDAC"), and in patients with Metastatic Castration-Resistant Prostate Cancer ("mCRPC") showing resistance to abiraterone.

Phase 1b/2 Clinical Trial in KRAS-mutated mCRC

TROV-054 is a Phase 1b/2 open-label multi-center clinical trial of onvansertib in combination with standard of care FOLFIRI and bevacizumab (Avastin ® ) for the second line treatment of patients with KRAS-mutated mCRC, which is being conducted at seven clinical trial sites across the U.S.

- USC Norris Comprehensive Cancer Center, The Mayo Clinic Cancer Centers (Arizona, Minnesota and Florida), Kansas University Medical Center, Inova Schar Cancer Institute and CARTI Cancer Center.

The primary objective of this trial is to evaluate the Dose-Limiting Toxicities ("DLTs") and maximum tolerated dose ("MTD") or recommended Phase 2 dose ("RP2D") of onvansertib in combination with FOLFIRI and bevacizumab (Phase 1b) and to continue to assess the safety and preliminary efficacy of onvansertib in combination with FOLFIRI and bevacizumab (Phase 2).

The scientific rationale for this clinical trial is based on the two key principles of synthetic lethality and synergy, with the objective of demonstrating a proof-of-concept of clinical benefit within this phase1b/2 trial.

Synthetic lethality refers to a critical vulnerability to tumor cell death by way of PLK1 inhibition within CRC tumor cells harboring KRAS mutations versus KRAS wild-type isogenic cells.

Synergy occurs when the combination of two drugs results in an unexpected greater activity than an expected additive effect of the two drugs.

Onvansertib in combination with two DNA-damaging agents, irinotecan and 5-FU (two components of FOLFIRI), demonstrated synergy in colorectal cancer cell lines and both combinations have demonstrated significantly greater tumor growth inhibition than either drug alone in CRC in vivo models.

We believe this synergy occurs because PLK1 can promote the repair of DNA damage caused by chemotherapeutic agents and by inhibiting PLK1, onvansertib leaves damaged tumor cells unable to replicate.

Data we presented on January 18, 2022 provided an update of the ongoing phase 1b/2 clinical trial in KRAS-mutated metastatic colorectal cancer.

• 12 of 35 (34%) patients treated per protocol at the RP2D in combination with FOLFIRI and bevacizumab achieved a Complete Response ("CR") or Partial Response ("PR") (CR:

11 patients);

• 17 of 48 (35%) patients across all dose levels achieved a CR or PR.

Historically, Objective Response Rates ("ORR") of 5-13% have been reported in similar second line patient populations treated with various different drug combinations, including the standard of care chemotherapy of FOLFIRI with bevacizumab;

• 5 of 48 (10%) patients discontinued the trial to pursue potentially curative metastasis-directed therapy (surgical resection or microwave ablation);

• Median Progression-Free Survival ("mPFS") across all response-evaluable patients (n=48) is 9.4 months and has not yet been reached in those treated per protocol at the RP2D.

Historically, mPFS of ~4.5-5.7 months has been reported in a similar patient population treated with standard of care chemotherapy of FOLFIRI with bevacizumab;

• The combination regimen of onvansertib plus FOLFIRI/bevacizumab is well tolerated with no major or unexpected toxicities attributed to onvansertib.

Phase 2 Clinical Trial in mPDAC

CRDF-001 is a Phase 2 open-label multi-center clinical trial of onvansertib in combination with nanoliposomal irinotecan (Onivyde ® ), leucovorin, and fluorouracil for second line treatment of patients with mPDAC, which is being conducted at six clinical trial sites across the U.S.

– The Mayo Clinic Cancer Centers (Arizona, Minnesota and Florida), Kansas University Medical Center, Inova Schar Cancer Institute, and the University of Nebraska Medical Center.

The first patient was dosed in June 2021.

The objective of this trial is to assess the safety and preliminary efficacy of onvansertib in combination with nanoliposomal irinotecan (Onyvide ® ), 5-FU and leucovorin as a second-line treatment in patients with mPDAC who have failed first-line gemcitabine-based therapy.

The trial is expected to enroll approximately 45 patients across six sites in the U.S.

including three of The Mayo Clinic Cancer Centers (Arizona, Minnesota and Florida), Kansas University Medical Center, Inova Schar Cancer Institute, and the University of Nebraska Medical Center.

Phase 2 Clinical Trial in mCRPC

TROV-053 is a Phase 2 open-label multi-center clinical trial of onvansertib in combination with abiraterone acetate (Zytiga ® ) and prednisone in patients with mCRPC, which is being conducted at three clinical trial sites - Beth Israel Deaconess Medical Center, Dana-Farber Cancer Institute and Massachusetts General Hospital.

The primary objective of this trial is to observe the effects of onvansertib in combination with abiraterone and prednisone on disease control as assessed by Prostate Specific Antigen ("PSA") decline or stabilization after 12 weeks of treatment in patients with mCRPC showing early signs of resistance to abiraterone.

The rationale for this trial is based on the Mechanism of Action ("MOA") of onvansertib and Zytiga ® and the synergy of these two drugs when used in combination in pre-clinical experiments.

Onvansertib inhibits tumor cell proliferation by inducing G2/M (mitosis) arrest and consequently cell death.

The combination of onvansertib and Zytiga ® synergistically increases mitotic arrest and cell death in prostate cancer cells and has demonstrated significantly greater tumor growth inhibition than either drug alone in vivo.

Data as of July 2, 2021, as follow-up to the data presented on February 11, 2021, at the American Society of Clinical Oncology Genitourinary Cancers Symposium (“ASCO-GU”) provided evidence of the safety and efficacy of onvansertib in combination with abiraterone.

Arms A (n=17) and B (n=20) and C (n=13) showed 29%, 40% and 54% of patients, respectively, achieving the primary endpoint of disease control at 12 weeks.

The more continuous dosing schedule of Arm C has shown an increase in the rate of patients achieving disease stabilization, to-date.

Evidence of efficacy was observed in patients harboring Androgen Receptor ("AR") alterations across all 3 arms.

Circulating Tumor DNA ("ctDNA") analysis revealed differences in baseline genomic profiles of patients achieving SD at 12 weeks vs.

patients progressing before or at 12 weeks.

Mutations exclusively present in patients with Stable Disease ("SD") were associated with cell cycle and DNA repair pathways that may result in increased sensitivity to onvansertib and efficacy of the combination.

Onvansertib plus abiraterone has demonstrated safety across all 3 dosing schedules.

Optimizing Drug Development with Correlative Biomarker Analysis using Circulating Tumor DNA

We have significant experience and expertise with biomarkers and technology in cancer.

In our ongoing clinical trial in KRAS-mutated mCRC, we are quantitatively assessing changes in the KRAS mutational burden with a simple blood test.

Decreases in KRAS mutant allelic frequency (MAF) after the first cycle of treatment are highly predictive of subsequent radiographic response observed as tumor shrinkage.

In our ongoing clinical trial in KRAS-mutated mCRC, we are quantitatively assessing changes in the KRAS mutational burden with a blood test based on ctDNA.

Decreases in KRAS Mutant Allelic Frequency ("MAF") in ctDNA after the first cycle of treatment were highly predictive of subsequent radiographic response observed as tumor shrinkage.

Technological advancements in the molecular characterization of cancers have enabled researchers to identify an increasing number of key molecular drivers of cancer progression.

These discoveries have led to multiple novel anticancer therapeutics and clinical benefit in selected patient populations.

As a clinical-stage biotechnology company developing new treatment options for cancer patients in indications with the greatest medical need, our objective is to optimize drug development by using our biomarker strategy as part of our approach.

These discoveries have led to the development of multiple novel anticancer therapeutics providing clinical benefit in selected patient populations.

As a clinical stage oncology company developing new precision medicine treatment options for cancer patients in indications with the greatest medical need, our objective is to optimize drug development by using our biomarker strategy as part of our approach.

Our laboratory in San Diego, California, enables us to optimize drug development and patient care.

In the clinical development of our drug candidate, onvansertib, correlative biomarker analyses are being used to help inform decisions in the evaluation of dose-response and optimal regimen for desired pharmacologic effect and safety.

Additionally, some biomarkers can be used as a surrogate endpoint for efficacy and/or toxicity, as well as predicting patients’ response by identifying certain patient populations that are more likely to respond to the drug therapy.

Additionally, some biomarkers can be used as a surrogate endpoint for efficacy and/or toxicity, as well as identifying certain patient populations that are more likely to respond to the drug therapy.

Operating Segment and Geographic Information

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Therefore, geographic information is not presented for revenues or long-lived assets.

We are a clinical-stage biotechnology company with our primary focus on the development of our drug candidate, onvansertib, a first-in-class, third generation, oral and highly selective PLK1 inhibitor to treat solid tumor cancers and hematologic malignancies.

There have been several drug candidates in this class of targeted oncology therapeutics to enter clinical trials;

however, we believe onvansertib is the only oral candidate currently in clinical trials and is differentiated from other ATP competitive inhibitors in that:

• its inhibition of PLK1 is highly-selective and the half maximal inhibitory concentration (IC 50 ) for PLK2 and PLK3 is over 5,000-fold of that for PLK1;

• it has a relatively short half-life of approximately 24 hours;

• it is available in an oral gelcap formulation;

• it allows for flexible dosing and scheduling;

• it has demonstrated safety, tolerability and preliminary efficacy;

• it is synergistic in combination with numerous chemotherapies and targeted therapeutics, which may enhance efficacy and duration of response.

The unacceptable toxicity of prior PLK inhibitors, such as volasertib from Boehringer Ingelheim, may be due to non-selective inhibition of PLK2 and PLK3 and a much longer half-life (approximately 135 hours) that could result in drug accumulation, which ultimately may have led to unsatisfactory clinical and safety outcomes.

In 2018, we initiated a Phase 1b/2 open-label clinical trial of onvansertib in combination with standard-of-care chemotherapy in AML patients to evaluate the safety/tolerability, determine the maximum tolerated dose (“MTD”), and assess preliminary efficacy.

This study is on file at ClinicalTrials.gov with the Identifier NCT03303339.

We also initiated a Phase 2 open-label clinical trial in patients with mCRPC in combination with Zytiga ® .

The mCRPC Phase 2 trial is on file at ClinicalTrials.gov with the Identifier NCT03414034.

In 2019 we initiated a Phase 1b/2 open-label clinical trial in mCRC in patients with a KRAS mutation in combination with FOLFIRI and Avastin ® in the second-line treatment setting.

This study is on file at ClinicalTrials.gov with the Identifier NCT03829410.

As of December 2020 we have four active IND applications in place with the FDA, one with the hematologic division and three with the solid tumor division.

This enables us to quickly initiate additional clinical trials of our drug candidate, onvansertib, in solid tumor cancers and hematologic malignancies.

Drug Development and Monitoring of Therapeutic Outcomes

Cell-free DNA diagnostic technology has significant potential as a simple, quick, noninvasive way of monitoring clinical responses to drugs in clinical development and evaluating patient-specific responses to already approved and marketed therapies.

Specific target applications include, but are not limited to, optimizing drug development to identify patients most likely to respond to targeted therapeutics.

One of the largest costs associated with development of a new therapy is the phases and size of human clinical studies required to identify the cohort of responders, and the resulting statistical power required.

By measuring specific genetic markers, it may be possible to pre-identify, and subsequently screen for, the most likely responders to the therapy, and to limit patient recruitment to this subset.

This strategy could significantly reduce the cost to develop a drug and improve development timelines.

We believe that there is significant research potential technology and expertise to be incorporated into ongoing and future clinical trial protocols, and ultimately into post-approval patient identification protocols.

Our Business Strategy

By integrating

biomarkers into our clinical development programs, we believe we will be able to identify patients who are most likely to respond to treatment.

Specifically, we are developing onvansertib, a first-in-class, third generation PLK1 inhibitor that targets mitosis (cell division) to treat a variety of cancers and associated indications.

Research and Development

We have historically made substantial investments in research and development.

Our research and development efforts are prioritized on the clinical development of our drug candidate, onvansertib, and our related biomarker assay development and pre-clinical research.

Our research and development team is composed of researchers and scientists (PhD’s), laboratory associate scientists, and experts in drug development and tumor genomics.

Research and development expenses for the years ended December 31, 2020 and 2019 were approximately $11.2 million and $11.2 million, respectively.

Metastatic Colorectal Cancer

Colorectal Cancer ("CRC") is a common cause of cancer death in the US.

The American Cancer Society's estimates for the number of CRC diagnoses in the US for 2020 were 104,610 new cases of colon cancer and 43,340 new cases of rectal cancer, with an estimated 53,200 deaths predicted during 2020.

Cancer‑specific mortality of CRC is predominantly due to metastatic disease.

Despite significant progress in the treatment of mCRC, the majority of patients with mCRC succumb to the disease.

RAS mutations in the CRC population are common, with greater than 50% of tumors from CRC patients harboring a RAS mutation (43% KRAS, 9% NRAS).

The efficacy of second-line therapy in terms of response and survival prolongation remains limited.

Therefore, improving the treatment options and effectiveness of treatment is critical to changing the outcomes for the KRAS-mutated patient population.

Collaborative Relationship

Pfizer Breakthrough Growth Initiative

In November 2021, we entered into a Securities Purchase Agreement (the “SPA”) with Pfizer Inc., as part of the Pfizer Breakthrough Growth Initiative, pursuant to which Pfizer purchased 2.4 million shares of our common stock at a purchase price per share of $6.22 for gross proceeds of approximately $15.0 million.

In connection with the purchase, Pfizer has agreed not to sell or transfer any of the shares, subject to certain customary exceptions, for a period of 180 days from the closing date of the SPA.

In connection with the stock purchase, we and Pfizer entered into an Information Rights Agreement pursuant to which Adam Schayowitz, Ph.D., MBA, Vice President & Medicine Team Group Lead for Breast Cancer, Colorectal Cancer and Melanoma at Pfizer will join our Scientific Advisory Board, and until May 17, 2023 we agreed to provide Pfizer with rights of first access to any pre-clinical or final clinical data and results generated as part of the onvansertib development program at least two business days prior to us providing such data to a third party.

Intellectual Property

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As of December 31, 2021, our owned and licensed intellectual property included 57 issued patents and 26 pending patent applications in the U.S.

and abroad, some of which are related to our legacy patent portfolio.

The pending patent applications include multiple international patent applications filed under the Patent Cooperation Treaty that may be used as the basis for multiple additional patent applications worldwide.

We plan to protect our intellectual property position by, among other things, licensing or filing our own U.S.

and foreign patent applications related to our proprietary technologies and products, and any inventions or improvements that are important to the development and implementation of our business.

We also may seek patent protection, if available, with respect to biomarkers and diagnostic methods that may be used to determine optimal patient populations for use of our product candidates.

Our license agreement with Nerviano dated March 15, 2017 grants us exclusive, worldwide licenses under a portfolio of three patent families of U.S.

We licensed onvansertib from Nerviano Medical Sciences ("NMS" or "Nerviano") pursuant to a license agreement with NMS dated March 13, 2017 which grants us exclusive, worldwide licenses under a portfolio of three patent families of U.S.

and foreign patents covering three broad areas:

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The license agreement covers the rights to develop combination therapies and identified predictive clinical biomarkers across cancer types, expanding potential indications for onvansertib.

Under the agreement, Cardiff Oncology has exclusive rights to develop, make, use, and sell combination therapies that include an anti-androgen or androgen antagonist and a PLK inhibitor for the treatment of cancer.

Under the agreement, we have exclusive rights to develop, make, use, and sell combination therapies that include an anti-androgen or androgen antagonist and a PLK inhibitor for the treatment of cancer.

The exclusive license agreement is part of our strategy to explore the efficacy of onvansertib in combination with anti-androgen drugs in cancers including prostate, breast, pancreatic, lung and gastrointestinal.

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9,566,280, by expanding the use of onvansertib to encompass combination therapies with any anti-androgen and androgen antagonist drug, such as Zytiga®, Xtandi® and Erleada® for the treatment of metastatic and non-metastatic castrate-resistant prostate cancer.

Our owned intellectual property included eight patent families related to onvansertib.

These families include patent applications directed to treating cancer using PLK1 inhibitors and determining efficacy of the treatment, treating benign prostatic hyperplasia using onvansertib, treating prostate cancer using PLK1 inhibitors, determining efficacy of PLK1 treatment based on biomarkers, and treating leukemia and lymphoma using combination therapies including a B-cell lymphoma 2 and a PLK1 inhibitor.

Our owned intellectual property includes twelve patent families related to onvansertib.

These families include patent applications directed to treating cancer using PLK1 inhibitors and determining efficacy of the treatment, treating benign prostatic hyperplasia using onvansertib, treating prostate cancer using PLK1 inhibitors, determining or predicting efficacies or responsiveness of PLK1 inhibitor treatments based on biomarkers, and treating cancers with combination therapies of PLK1 inhibitors (including treating leukemia and lymphoma using combination therapies of B-cell lymphoma 2 and PLK1 inhibitors).

Any patents issued in these families will expire between 2039 and 2042.

One of the patent families includes patent applications

directed to selecting and treating cancers with combination therapies of PLK1 inhibitors.

MIT and we co-own this family.

On November 17, 2021, we amended the Exclusive Patent License Agreement with MIT to include this patent family.

Wherever possible, we seek to protect our inventions by filing U.S.

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Manufacturing and Distribution

We have a supply agreement with NerPharMa, S.r.l., a GMP and FDA validated pharmaceutical manufacturing company and a subsidiary of Nerviano, to manufacture drug product for onvansertib.

The agreement covers the clinical and commercial supply of onvansertib, and includes both Active Pharmaceutical Ingredients (“API”) and Good Manufacturing Process (“GMP”) production of capsules.

We have a supply agreement with NerPharMa, S.r.l., a Good Manufacturing Process ("GMP") and U.S Food and Drug Administration ("FDA") validated pharmaceutical manufacturing company and a subsidiary of Nerviano, to manufacture drug product for onvansertib.

The agreement covers the clinical supply of onvansertib, and includes both Active Pharmaceutical Ingredients (“API”) and Current Good Manufacturing Process (“CGMP”) production of capsules.

We have a master services agreement with Unión Químico Farmacéutica SAU ("Uquifa") and its associate company Soneas Chemicals Ltd.

Uquifa is a European leader in contract development and manufacturing for small molecule API’s, to perform Regulatory Starting Materials ("RSMs") and API CGMP manufacturing and other services as agreed to.

We have a statement of work with Lonza, a world-wide manufacturer and developer of small molecules, to provide cGMP manufacturing and packaging services for our clinical trials.

Government Regulation

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Failure to comply with applicable U.S.

requirements may subject a company to a variety of administrative or judicial sanctions, such as FDA refusal to approve pending new drug applications (“NDAs”) or biologic license applications (“BLAs”) warning letters, product recalls, product seizures, total or partial suspension of production or distribution, injunctions, fines, civil penalties, and criminal prosecution.

Pharmaceutical product development in the United States typically involves preclinical laboratory and animal tests, the submission to the FDA of an IND, which must become effective before clinical testing may commence, and adequate and well-controlled clinical trials to establish the safety and effectiveness of the drug or biologic for each indication for which FDA approval is sought.

requirements may subject a company to a variety of administrative or judicial sanctions, such as FDA refusal to approve pending New Drug Applications (“NDAs”) or Biologics License Applications (“BLAs”) warning letters, product recalls, product seizures, total or partial suspension of production or distribution, injunctions, fines, civil penalties, and criminal prosecution.

Pharmaceutical product development in the United States typically involves preclinical laboratory and animal tests, the submission to the FDA of an Investigational New Drug Application ("IND"), which must become effective before clinical testing may commence, and adequate and well-controlled clinical trials to establish the safety and effectiveness of the drug or

biologic for each indication for which FDA approval is sought.

Satisfaction of FDA pre-market approval requirements typically takes many years and the actual time required may vary substantially based upon the type, complexity and novelty of the product or disease.

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Additionally, the FDA will inspect the facility or the facilities at which the drug product is manufactured.

The FDA will not approve the NDA or, in the case of a biologic, the BLA unless compliance with Current Good Manufacturing Process ("CGMPs") is satisfactory and the marketing application contains data that provide substantial evidence that the product is safe and effective in the indication studied.

The FDA will not approve the NDA or, in the case of a biologic, the BLA unless compliance with CGMPs is satisfactory and the marketing application contains data that provide substantial evidence that the product is safe and effective in the indication studied.

Manufacturers of biologics also must comply with FDA’s general biological product standards.

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The FDA has committed to reviewing such resubmissions in two or six months depending on the type of information included.

It is not unusual for the FDA to issue a complete response letter

because it believes that the drug product is not safe enough or effective enough or because it does not believe that the data submitted are reliable or conclusive.

It is not unusual for the FDA to issue a complete response letter because it believes that the drug product is not safe enough or effective enough or because it does not believe that the data submitted are reliable or conclusive.

An approval letter authorizes commercial marketing of the drug product with specific prescribing information for specific indications.

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Healthcare providers, physicians and third-party payors play a primary role in the recommendation and prescription of drug and biologic product candidates which obtain marketing approval.

In addition to FDA restrictions on marketing of pharmaceutical products, pharmaceutical manufacturers are exposed, directly, or indirectly, through customers, to broadly applicable fraud and abuse and other healthcare laws and regulations that may affect the business or financial arrangements and relationships through which a pharmaceutical manufacturer can market, sell and distribute drug and biologic products.

In addition to FDA restrictions on marketing of

pharmaceutical products, pharmaceutical manufacturers are exposed, directly, or indirectly, through customers, to broadly applicable fraud and abuse and other healthcare laws and regulations that may affect the business or financial arrangements and relationships through which a pharmaceutical manufacturer can market, sell and distribute drug and biologic products.

These laws include, but are not limited to:

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The term “remuneration” has been broadly interpreted to include anything of value.

This statute has been interpreted to apply to arrangements between pharmaceutical manufacturers on one hand and

prescribers, purchasers, and formulary managers on the other hand.

This statute has been interpreted to apply to arrangements between pharmaceutical manufacturers on one hand and prescribers, purchasers, and formulary managers on the other hand.

Although there are a number of statutory exemptions and regulatory safe harbors protecting certain common activities from prosecution, the exemptions and safe harbors are drawn narrowly, and practices that involve remuneration intended to induce prescribing, purchases, or recommendations may be subject to scrutiny if they do not qualify for an exemption or safe harbor.

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Because of the breadth of these laws and the narrowness of the safe harbors, it is possible that some business activities can be subject to challenge under one or more of such laws.

The scope and enforcement of each of these laws is uncertain and subject to rapid change in the current environment of healthcare reform, especially in light of the lack of applicable precedent

and regulations.

The scope and enforcement of each of these laws is uncertain and subject to rapid change in the current environment of healthcare reform, especially in light of the lack of applicable precedent and regulations.

Federal and state enforcement bodies have recently increased their scrutiny of interactions between healthcare companies and healthcare providers, which has led to a number of investigations, prosecutions, convictions and settlements in the healthcare industry.

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• an increase in the statutory minimum rebates a manufacturer must pay under the Medicaid Drug Rebate Program, to 23.1% and 13% of the average manufacturer price for most branded and generic drugs, respectively and capped the total rebate amount for innovator drugs at 100% of the Average Manufacturer Price (“AMP”);

• a new methodology by which rebates owed by manufacturers under the Medicaid Drug Rebate Program are calculated for certain drugs and biologics, including our product candidates, that are inhaled, infused, instilled, implanted or injected;

• a new methodology by which rebates owed by manufacturers under the Medicaid Drug Rebate Program are calculated for certain drugs and biologics, including our product candidate, that are inhaled, infused, instilled, implanted or injected;

• extension of manufacturers’ Medicaid rebate liability to covered drugs dispensed to individuals who are enrolled in Medicaid managed care organizations;

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It is also possible that other legislative proposals having similar effects will be adopted.

Furthermore, regulatory authorities’ assessment of the data and results required to demonstrate safety and efficacy can change over time and can be affected by many factors, such as the emergence of new information, including on other products, changing policies and agency funding, staffing and leadership.

No one can be sure whether future changes to the regulatory environment will be favorable or unfavorable to business prospects.

For example, average review times at the FDA for marketing approval applications can be affected by a variety of factors, including budget and funding levels and statutory, regulatory and policy changes.

Regulation in the European Union

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If this procedure is not used, approval in one country of the European Union can be used to obtain approval in another country of the European Union under two simplified application processes, the mutual recognition procedure or the decentralized procedure, both of which rely on the principle of mutual recognition.

After receiving regulatory approval through any of the European registration procedures, pricing and reimbursement approvals are also required in most countries.

After receiving

regulatory approval through any of the European registration procedures, pricing and reimbursement approvals are also required in most countries.

Other Regulations

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As a result, the development of orphan drugs continues to grow at a faster rate than the development of traditional pharmaceuticals.

The FDA granted Orphan Drug Designation (“ODD”) to onvansertib in the treatment of AML in October 2017.

The FDA granted Orphan Drug Designation (“ODD”) to onvansertib in the treatment of Acute Myeloid Leukemia ("AML") in October 2017.

The European Commission granted ODD to onvansertib in the treatment of AML in Europe in August 2018.

Onvansertib is not the first PLK inhibitor that has entered clinical development;

however, we believe it currently is the only oral PLK1 inhibitor in active clinical development and delivers highly selective PLK1 inhibition.

however, we believe it currently is the only oral PLK1 inhibitor in active clinical development that delivers highly selective PLK1 inhibition.

Onvansertib is also synergistic in combination with numerous chemotherapies and targeted therapeutics and may enhance and/or extend response to treatment across a number of solid tumor cancers and hematologic malignancies.

A Phase 1 trial in advanced metastatic solid tumor cancers has been completed and published in Investigational New Drugs.

A Phase 1b/2 trial in AML was initiated in November 2017, with the first patient treated in February, 2018 and a total of eight sites participating.

A Phase 1b/2 trial in AML was initiated in November 2017, with the first patient treated in February, 2018 and the last patient completed treatment in November, 2021.

A Phase 2 trial in mCRPC was initiated in June, 2018 with the Harvard Medical Cancer Centers - Beth Israel Deaconess Medical Center, Dana Farber Cancer Institute and Massachusetts General Hospital - with the first patient treated in August, 2018.

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At the end of 2020 and early 2021, five additional sites were added including The Mayo Clinics (Minnesota and Florida), CARTI Cancer Center, Kansas University Medical Center and Inova Schar Cancer Institute.

A Phase 2 trial in mPDAC was initiated in May, 2021 with the The Mayo Clinics (Arizona, Minnesota and Florida), Inova Schar Cancer Institute and Kansas University Medical Center – with the first patient treated in June, 2021.

The most prominent PLK inhibitor tested in late-stage clinical development, thus far, is volasertib, developed by Boehringer Ingelheim.

In a randomized Phase 2 trial of volasertib plus LDAC in 87 AML patients not eligible for induction therapy, patients received LDAC 20mg twice-daily subcutaneously on days 1-10 or LDAC plus volasertib 350 mg IV on days 1 + 15 every four weeks.

The response rate (complete remission and complete remission with incomplete blood count recovery) was higher for LDAC + volasertib vs LDAC (31.0% vs 13.3%;

Median event-free survival was significantly prolonged by LDAC + volasertib compared with LDAC (5.6 vs 2.3 months).

The response rate (complete remission and complete remission with incomplete blood count recovery) was higher for LDAC + volasertib vs.

LDAC (31.0% vs.

Median event-free survival was significantly prolonged by LDAC + volasertib compared with LDAC (5.6 vs.

The encouraging results led to the Phase 3 POLO-AML-2 study in early 2013, which enrolled 666 elderly patients (65 years or older) with newly diagnosed AML, who were not eligible for intensive induction therapy.

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By contrast, onvansertib is able to deliver much more selective inhibition of PLK1 than volasertib.

Onvansertib also has a half-life of 24 hours vs volasertib’s 135 hours and it is orally administered.

Onvansertib also has a half-life of 24 hours vs.

volasertib’s 135 hours and it is orally administered.

GSK461364, developed by GSK, appears to have less sensitivity to PLK2 and PLK3 than volasertib, although it is not as specific to PLK1 as onvansertib.

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Venous Thrombotic Emboli (VTE) and myelosuppression were the most common grade 3-4 drug-related events;

and VTE occurred in 20% of patients, which demanded co-administration of anticoagulants.

and VTE occurred in 20% of patients, which

demanded co-administration of anticoagulants.

The trial was completed in 2009 and there are no further clinical updates for GSK461364 after the Phase 1 study.

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Rigosertib, a non-targeted broad-spectrum multi-kinase inhibitor (RAF, PI3K, PLK), was evaluated for Myelodysplastic Syndrome (“MDS”) and failed to achieve the primary endpoint of overall survival in a Phase 3 trial (2020).

CY140, an inhibitor of PLK1, PLK2 and PLK3, is currently in a phase 1 first-in-human study for advanced leukemias and MDS (2020).

CY140, an inhibitor of PLK1, PLK2 and PLK3, is currently in planning stages for phase 1/2 studies in solid tumors and leukemias (2022) .

Human Capital

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In January 2010, we re-incorporated under the laws of the State of Delaware and changed our name to Trovagene, Inc.

In May 2012, our common stock was listed on The Nasdaq Capital Market under the ticker symbol TROV.

In May 2012, our common stock was listed on The Nasdaq Capital Market ("Nasdaq") under the ticker symbol TROV.

In May 2020 we changed our name to Cardiff Oncology, Inc.

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Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business