The purpose of the Phase 1b/2 study is to determine the safety and efficacy of Onvansertib,
administered orally, daily, for 5 consecutive days on Day 1-5 of each 14-day course in each
28-day cycle, in combination with FOLFIRI + Avastin, as second-line treatment in adult
patients who have metastatic colorectal cancer with a Kras mutation. Participants must have
histologically confirmed metastatic and unresectable disease, and previously failed treatment
or be intolerant to fluoropyrimidine and oxaliplatin with or without bevacizumab.
1. Histologically confirmed metastatic and unresectable CRC.
2. Kras mutation in exon 2, 3 or 4 in primary tumor or metastasis, assessed by a
CLIA-certified lab. Subjects with concomitant Kras and BRAF-V600 utations are excluded
from this study. Subjects with MSI-H/ddMMR (Microsatellite Instability High/Deficient
Mismatch Repair) are also ineligible for enrollment in this study.
3. Age ≥ 18 years.
4. ECOG Performance Status of 0 or 1.
5. Subject is not receiving any other cancer therapy. Patients participating in surveys
or observational studies are allowed.
6. Has failed treatment or is intolerant of fluoropyrimidine and oxaliplatin with or
6a. All patients must have received a minimum of 6 weeks of the first line regimen that
included oxaliplatin and a fluoropyrimidine with or without bevacizumab in the same cycle.
Treatment failure is defined as radiologic progression during or < 6 months after the last
dose of first-line therapy.
6b. Patients who show tumor progression while on maintenance therapy with a
fluoropyrimidine with or without bevacizumab after prior fluoropyrimidine-oxaliplatin with
or without bevacizumab induction therapy are eligible. Rechallenge with oxaliplatin is
permitted and will be considered part of the first-line regimen for metastatic disease,
with both initial oxaliplatin treatment and subsequent rechallenge being considered as one
6c. Patients who received oxaliplatin/fluoropyrimidine-based neoadjuvant or adjuvant
therapy and have disease recurrence or progression > 6 months from their last dose of
neoadjuvant or adjuvant treatment (or > 6 months from surgery if no adjuvant therapy was
administered) will be required to receive fluoropyrimidine/oxaliplatin-based therapy with
or without bevacizumab for metastatic disease.
6d. For participants with rectal cancer, sequential neoadjuvant and adjuvant therapy will
count as a single systemic regimen.
6e. Patients who discontinued first-line therapy because of toxicity may be enrolled for as
long as progression occurred < 6 months after the last dose of first-line therapy.
7. FOLFIRI therapy is appropriate for the patient as determined by the Investigator.
8. WOCBP must have a negative serum or urine pregnancy test within 5 days prior to
8a. WOCBP include any female who has experienced menarche and who has not undergone
successful surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral
oophorectomy) or is not postmenopausal (defined as amenorrhea > 12 consecutive months); or
women on hormone replacement therapy (HRT) with documented serum follicle stimulating
hormone (FSH) level > 35 mIU/mL. Even women who are using oral, implanted or injectable
contraceptive hormones or mechanical products such as an IUD or barrier methods (diaphragm,
condoms, spermicides) to prevent pregnancy or practicing abstinence or where partner is
sterile (e.g., vasectomy), should be considered to be of child-bearing potential.
9. Imaging CT/MRI of chest/abdomen/pelvis or other scans as necessary to document all sites
of disease performed within 21 days prior to enrollment. Only patients with measurable
disease are eligible for enrollment.
10. Must have acceptable organ function. 11. Patient must consent to provision of, and
Investigator(s) must confirm access to and agree to submit a representative, formalin
fixed, paraffin block of tumor tissue to be used for correlative marker assays. Submission
of the tissue does not have to occur prior to enrollment.
12. Signed informed consent to provide blood sample(s) for specific correlative assays.
1. Concomitant Kras and BRAF-V600 mutations or MSI-H/dMMR (Microsatellite Instability
High/Deficient Mismatch Repair)
2. Anti-cancer chemotherapy or biologic therapy administered within 4 weeks prior to the
first dose of study drug. The exception is a single dose of radiation up to 8 Gray
(equal to 800 RAD) with palliative intent for pain control up to 14 days before
3. More than one prior chemotherapy regimen administered in the metastatic setting.
4. Major surgery within 6 weeks prior to randomization.
5. Untreated brain metastasis.
6. Women who are pregnant or breastfeeding.
7. Gastrointestinal (GI) disorder(s) that, in the opinion of the Investigator, would
significantly impede the absorption of an oral agent (e.g., intestinal occlusion,
active Crohn's disease, ulcerative colitis, extensive gastric and small intestine
8. Unable or unwilling to swallow study drug.
9. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, clinically significant non-healing or healing wounds, symptomatic
congestive heart failure (CHF) Class II or higher according to the New York Heart
Association (NYHA) Functional Classification), unstable angina pectoris, clinically
significant cardiac arrhythmia, significant pulmonary disease (shortness of breath at
rest or mild exertion), uncontrolled infection or psychiatric illness/social
situations that would limit compliance with study requirements.
9a. Known active infection with Human Immunodeficiency Virus (HIV), with measurable viral
titer, and/or active infection with hepatitis B or C (patients who have had a hepatitis B
virus [HBV] immunization are eligible).
9b. Clinically significant ascites or pleural effusions. 10. Known hypersensitivity to
5-fluorouracil/leucovorin. 11. Known hypersensitivity to irinotecan. 12. Abnormal
glucuronidation of bilirubin, known Gilbert's syndrome. 13. Patients with a history of
other malignancies except: adequately treated non-melanoma skin cancer, curatively treated
in-situ cancer of the cervix, or other solid tumors curatively treated with no evidence of
disease for > 2 years.
14. Any active disease condition that would render the protocol treatment dangerous or
impair the ability of the patient to receive study drug.
15. Planned concomitant use of medications known to prolong the QT/QTc interval.
16. Presence of risk factors for torsade de pointes, including family history of Long QT
Syndrome or uncorrected hypokalemia.
17. The following are exclusion criteria for bevacizumab: 17a. History of cardiac disease:
congestive heart failure (CHF) Class II or higher according to the New York Heart
Association (NYHA); active coronary artery disease, myocardial infarction within 6 months
prior to study entry; unevaluated new onset angina within 3 months or unstable angina
(angina symptoms at rest) or cardiac arrhythmias requiring anti arrhythmic therapy (beta
blockers or digoxin are permitted).
17b. Current uncontrolled hypertension (systolic blood pressure [BP] > 150 mmHg or
diastolic pressure > 90 mmHg despite optimal medical management) and prior history of
hypertensive crisis or hypertensive encephalopathy.
17c. History of arterial thrombotic or embolic events (within 6 months prior to study
17d. Significant vascular disease (e.g., aortic aneurysm, aortic dissection, symptomatic
peripheral vascular disease).
17e. Evidence of bleeding diathesis or clinically significant coagulopathy. 17f. Major
surgical procedure (including open biopsy, significant traumatic injury, etc.) within 28
days, or anticipation of the need for major surgical procedure during the study, and minor
surgical procedure (excluding placement of a vascular access device) within 7 days prior to
17g. Proteinuria at Screening as demonstrated by urinalysis with proteinuria ≥ 2+ (patients
discovered to have ≥ 2+ proteinuria on dipstick urinalysis at baseline should undergo a
24-hour urine collection and must demonstrate ≤ 1g of protein in 24 hours to be eligible).
17h. History of abdominal fistula, GI perforation, peptic ulcer, or intra-abdominal abscess
within 6 months.
17i. Ongoing serious, non-healing wound, ulcer, or bone fracture. 17j. Known
hypersensitivity to any component of bevacizumab. 17k. History of reversible posterior
leukoencephalopathy syndrome (RPLS).