IRB Study Number 24-693
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary Objectives
To assess the efficacy of 2 different doses of onvansertib in combination with FOLFIRI and bevacizumab or FOLFOX and bevacizumab for treatment of confirmed metastatic and unresectable CRC in patients with a KRAS or NRAS mutation in the first-line setting.
Secondary Objectives
To assess the durability of response of 2 different doses of onvansertib in combination with FOLFIRI and bevacizumab or FOLFOX and bevacizumab.
To assess the safety, efficacy, PK, and pharmacodynamic of 2 different doses of onvansertib in combination with FOLFIRI and bevacizumab or FOLFOX and bevacizumab.
Inclusion Criteria
Histologically confirmed metastatic CRC.
Documentation of a KRAS or NRAS mutation in exon 2, 3, or 4 in the primary tumor or metastasis, assessed by liquid biopsy or histological report.
No previous systemic therapy in the metastatic setting. Note: participants who complete prior neoadjuvant or adjuvant chemotherapy and present with reoccurrence/metastatic disease within 6 months of stopping treatment will count as having 1 line of prior therapy in the metastatic setting.
Patient must be willing to submit archival tissue or undergo a fresh biopsy prior to starting treatment. If the patient submitted tissue during the prescreening period, then additional tissue is not required.
Age ≥ 18 years.
ECOG performance status of 0 or 1 (Appendix 16.2).
A woman of childbearing potential (WOCBP) or a male with a female partner who is a WOCBP must agree to use contraception or take measures to avoid pregnancy during the study and for 180 days after the final dose of any study drug.
a. A WOCBP includes 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 with documented serum follicle stimulating hormone 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 (eg, vasectomy), should be considered to be of childbearing potential.
b. A WOCBP must have a negative serum or urine pregnancy test within 5 days prior to enrollment.
c. Adequate contraception is defined as follows:
I. Complete true abstinence.
II. Consistent and correct use of 1 of the following methods of birth control:
Male partner who is sterile prior to the female patient’s entry into the study and is the sole sexual partner for that female patient.
Implants of levonorgestrel.
Injectable progestogen.
Intrauterine device (IUD) with a documented failure rate of < 1% per year.
Oral contraceptive pill (either combined or progesterone only).
Barrier method, for example: diaphragm with spermicide or condom with spermicide in combination with either implants of levonorgestrel or injectable progestogen.
Imaging computed tomography (CT) or magnetic resonance imaging (MRI) of chest/abdomen/pelvis and other scans as necessary to document all sites of disease performed within 28 days prior to the first dose of onvansertib. Only patients with measurable disease as defined per RECIST v1.1 are eligible for enrollment. CT is the preferred imaging modality, but MRI is also accepted. All subsequent scans must consistently use the same imaging modality for comparison with the Screening scan throughout the study.
Must have acceptable organ function as detailed in Table 4-1: (See protocol)
Exclusion Criteria
Concomitant KRAS or NRAS and BRAF-V600 mutation or microsatellite instability high/deficient mismatch repair.
Prior treatment with a VEGF inhibitor, including bevacizumab or biosimilars.
Previous oxaliplatin treatment within 12 months prior to randomization, when oxaliplatin-containing arms are open for enrollment.
Known dihydropyrimidine dehydrogenase (DPD) deficiency; refer to local fluorouracil or capecitabine label or local clinical guidance, for DPD status recommendation prior to starting treatment.
Anticancer chemotherapy or biologic therapy administered within 28 days 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 enrollment, provided it is not the target lesion.
Untreated or symptomatic brain metastasis.
Women who are pregnant or breastfeeding.
Gastrointestinal (GI) disorder(s) that, in the opinion of the Investigator, would significantly impede the absorption of an oral agent (eg, intestinal occlusion, active Crohn’s disease, ulcerative colitis, extensive gastric and small intestine resection).
Unable or unwilling to swallow study drug.
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 (see bevacizumab cardiac exclusions below), 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.
a. Known active infection with HIV, with measurable viral titer, and/or active infection with hepatitis B or C (patients who have had a hepatitis B virus immunization are eligible).
b. Known active infection with SARS-CoV-2 where symptoms are present and considered clinically significant per the treating investigator.
c. Clinically significant ascites or pleural effusions.
Known hypersensitivity to fluoropyrimidine or leucovorin.
Known hypersensitivity to irinotecan.
Known hypersensitivity to oxaliplatin.
Abnormal glucuronidation of bilirubin; known Gilbert’s syndrome.
Patients with a history of other malignancies except adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix or prostate, or other solid tumors curatively treated with no evidence of disease for > 2 years. Participants with a history of other curatively treated malignancies with low risk of recurrence not listed may also be considered eligible after consultation with Sponsor or designee.
Any active disease condition that would render the protocol treatment dangerous or impair the ability of the patient to receive study drug.
Any condition (eg, psychological, geographical, etc.) that does not permit compliance with the protocol.
Treatment with any of the drugs listed in Section 5.6 at the time of study treatment initiation.
QT interval:
a. QT interval using Fridericia’s correction (QTcF) > 470 milliseconds. The QTcF should be calculated as the arithmetic mean of the QTcF on triplicate ECGs. In the case of potentially correctible causes of QT prolongation that are readily corrected (eg, medications, hypokalemia), the triplicate ECG may be repeated once during Screening and that result may be used to determine eligibility.
b. Planned concomitant use of medications known to prolong the QT/QTc interval according to institutional guidelines.
c. Presence of risk factors for torsade de pointes, including family history of Long QT Syndrome or uncorrected hypokalemia.
d. Patients with pacemakers will be excluded.
Use of strong CYP3A4 or CYP2C19 inhibitors or strong CYP3A4 inducers. Patients currently receiving these agents who can be switched to alternate therapy are not excluded. Inhibitors should be stopped at least 1 week prior to the first dose of protocol therapy and inducers should be stopped at least 2 weeks prior to initiation of protocol therapy.
The following are exclusion criteria for bevacizumab:
a. History of cardiac disease: CHF Class II or higher according to the 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, with the exception of patients who have been receiving therapy and are deemed by the Investigator to have stable/controlled disease.
b. Current uncontrolled hypertension (systolic blood pressure >150 mmHg or diastolic blood pressure >90 mmHg despite optimal medical management) and prior history of hypertensive crisis or hypertensive encephalopathy.
c. History of arterial thrombotic or embolic events (within 6 months prior to study entry).
d. Significant vascular disease (eg, aortic aneurysm, aortic dissection, symptomatic peripheral vascular disease).
e. Evidence of bleeding diathesis or clinically significant coagulopathy.
f. 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 study enrollment.
g. 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 ≤1 g of protein in 24 hours to be eligible).
h. Abdominal fistula, GI perforation, peptic ulcer, or intra-abdominal abscess within the past 6 months.
i. Ongoing serious, non-healing wound, ulcer, or bone fracture
j. Known hypersensitivity to any component of bevacizumab
k. History of reversible posterior leukoencephalopathy syndrome
