Clinical trial NCT05593328: Study of Onvansertib in Combination With FOLFIRI and Bevacizumab Versus FOLFIRI and Bevacizumab for Second Line Treatment of Metastatic Colorectal Cancer in Participants With a Kirsten Rat Sarcoma Virus Gene (KRAS) or Neuroblastoma-RAS (NRAS) Mutation
Official title: A Phase 2, Randomized, Open-label Study of Onvansertib in Combination With FOLFIRI and Bevacizumab Versus FOLFIRI and Bevacizumab for Second Line Treatment of Metastatic Colorectal Cancer in Patients With a KRAS or NRAS Mutation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Colorectal Cancer
Metastatic Colorectal Cancer
Keywords: Colorectal Cancer
Metastatic Colorectal Cancer
KRAS Mutation
NRAS Mutation
Onvansertib
FOLFIRI
Bevacizumab
Lead sponsor: Cardiff Oncology
Sponsor class: INDUSTRY
First posted: 2022-10-25
Enrollment: 23
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The primary objective of this study is to assess the efficacy of 2 different doses of onvansertib in combination with a chemotherapy regimen of irinotecan, fluorouracil \[5-FU\], and leucovorin (FOLFIRI) and bevacizumab for treatment of confirmed metastatic and/or unresectable colorectal cancer (CRC) in participants with a kirsten rat sarcoma virus gene (KRAS) or neuroblastoma-RAS (NRAS) mutation who have progressed on an oxaliplatin/fluoropyrimidinebased regimen in the first-line setting.


Eligibility criteria: Inclusion Criteria:

1. Histologically confirmed metastatic and/or unresectable colorectal cancer (CRC).
2. Documentation of a kirsten rat sarcoma virus gene (KRAS) or neuroblastoma-RAS (NRAS) mutation in exon 2, 3, or 4 in primary tumor or metastasis, assessed by a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory.
3. Age ≥ 18 years.
4. Participants with tumors that have progressed on an oxaliplatin/fluoropyrimidine--based regimen with or without bevacizumab.

   1. Participants must have had systemic therapy within 180 days of the screening visit.
   2. Participants must have, at any time previously, received oxaliplatin-based chemotherapy with or without bevacizumab (≥ 6 weeks in duration).
   3. Participants who received oxaliplatin/fluoropyrimidine-based neoadjuvant, adjuvant, and/or fluoropyrimidine maintenance or adjuvant therapy and have disease recurrence or progression \> 6 months from their last dose of oxaliplatin will be required to have received oxaliplatin/fluoropyrimidine-based therapy with or without bevacizumab as first-line treatment for metastatic disease.
   4. Participants who received an oxaliplatin-based regimen in the first-line setting and discontinued oxaliplatin because of toxicity or who received oxaliplatin for maintenance therapy are eligible as long as progression occurred \< 6 months after the last dose of oxaliplatin therapy for advanced metastatic disease. It is recommended that these participants be re-challenged (if feasible) with oxaliplatin/fluoropyrimidine therapy and subsequently progress prior to eligibility. Participants with oxaliplatin-related neuropathy or oxaliplatin infusion-related hypersensitivity that cannot be rechallenged with oxaliplatin are eligible.
5. Participants must not have received prior treatment with irinotecan.
6. FOLFIRI therapy is appropriate for the participant as determined by the Investigator.
7. Imaging computed tomography (CT) or magnetic resonance imaging (MRI) of chest/abdomen/pelvis or other scans as necessary to document all sites of disease performed within 28 days prior to the first dose of onvansertib. Only participants with measurable disease as defined per Response Evaluation Criteria in Solid Tumors Version 1.1 (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.
8. Must have acceptable organ function
9. Signed informed consent to provide blood sample(s) for specific correlative assays

Exclusion Criteria:

1. Concomitant KRAS or NRAS and BRAF-V600 mutation or Microsatellite Instability High/Deficient Mismatch Repair (MSI-H/dMMR).
2. Anti-cancer 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.
3. More than 1 prior chemotherapy regimen administered in the metastatic setting.
4. Major surgery within 6 weeks prior to enrollment.
5. Untreated or symptomatic brain metastasis.
6. 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 resection).
7. Unable or unwilling to swallow study drug.
8. Known hypersensitivity to fluoropyrimidine or leucovorin.
9. Known hypersensitivity to irinotecan.
10. Abnormal glucuronidation of bilirubin; known Gilbert's syndrome.
11. QT interval:

    1. Fridericia's correction (QTcF) \> 470 milliseconds. The QTcF should be calculated as the arithmetic mean of the QTcF on triplicate electrocardiograms (ECGs). In the case of potentially correctible causes of QT prolongation that are readily corrected (e.g., medications, hypokalemia), the triplicate ECG may be repeated once during Screening and that result may be used to determine eligibility.
    2. Planned concomitant use of medications known to prolong the QT/QTc interval according to institutional guidelines.
    3. Presence of risk factors for torsade de pointes, including family history of Long QT Syndrome or uncorrected hypokalemia.
12. Use of strong cytochrome P450 3A4 (CYP3A4) or cytochrome P450 2C19 (CYP2C19) inhibitors or strong CYP3A4 inducers. Participants 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.
13. The following are exclusion criteria for bevacizumab:

    1. 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, with the exception of participants who have been receiving therapy and are deemed by the Investigator to have stable/controlled disease.
    2. 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.
    3. History of arterial thrombotic or embolic events (within 6 months prior to study entry).
    4. Significant vascular disease (eg, aortic aneurysm, aortic dissection, symptomatic peripheral vascular disease).
    5. Evidence of bleeding diathesis or clinically significant coagulopathy.
    6. 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.
    7. Proteinuria at Screening as demonstrated by urinalysis with proteinuria ≥2+ (participants 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).
    8. Abdominal fistula, gastrointestinal perforation, peptic ulcer, or intra-abdominal abscess within the past 6 months.
    9. Ongoing serious, non-healing wound, ulcer, or bone fracture
    10. Known hypersensitivity to any component of bevacizumab
    11. History of reversible posterior leukoencephalopathy syndrome

Primary outcomes:
measure: Overall Response Rate
timeFrame: Up to approximately 1 year
Secondary outcomes:
measure: Progression-free Survival (PFS)
timeFrame: Up to approximately 1 year
measure: Number of Participants with an Adverse Event (AE)
timeFrame: Up to approximately 1 year
measure: Disease Control Rate (DCR)
timeFrame: Up to approximately 1 year
measure: Duration of Response (DOR)
timeFrame: Up to approximately 1 year
measure: Overall Survival (OS)
timeFrame: Up to approximately 1 year
measure: Overall Response (OR)
timeFrame: Up to approximately 1 year
measure: Maximum Concentration (Cmax) of Onvansertib
timeFrame: Day 1 and Day 5 of Cycle 1, and Day 5 of Cycle 3 (cycle is 28 days)
measure: Area Under The Plasma Concentration Curve (AUC) of Onvansertib
timeFrame: Day 1 and Day 5 of Cycle 1, and Day 5 of Cycle 3 (cycle is 28 days)
measure: Trough Concentration (Ctrough) of Onvansertib
timeFrame: Day 1 and Day 5 of Cycle 1, and Day 5 of Cycle 3 (cycle is 28 days)
measure: Maximum Concentration (Cmax) of Onvansertib Metabolites
timeFrame: Day 1 and Day 5 of Cycle 1, and Day 5 of Cycle 3 (cycle is 28 days)
measure: Area Under The Plasma Concentration Curve (AUC) of Onvansertib Metabolites
timeFrame: Day 1 and Day 5 of Cycle 1, and Day 5 of Cycle 3 (cycle is 28 days)
measure: Trough Concentration (Ctrough) of Onvansertib Metabolites
timeFrame: Day 1 and Day 5 of Cycle 1, and Day 5 of Cycle 3 (cycle is 28 days)
measure: Efficacy: Exposure Response Evaluation of Onvansertib
timeFrame: Up to approximately 1 year
measure: Safety: Exposure Response Evaluation of Onvansertib
timeFrame: Up to approximately 1 year
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Mayo Clinic in Arizona - Phoenix Campus
state: Arizona
city: Little Rock
country: United States
facility: Central Arkansas Radiation Therapy Institute - Cancer Center
state: Arkansas
city: Anaheim
country: United States
facility: Pacific Cancer Medical Center
state: California
city: Bakersfield
country: United States
facility: Comprehensive Blood and Cancer Center - Bakersfield
state: California
city: Los Alamitos
country: United States
facility: Cancer and Blood Specialty Clinic
state: California
city: Los Angeles
country: United States
facility: Norris Comprehensive Cancer Center
state: California
city: Orange
country: United States
facility: UCI Health - Chao Family Comprehensive Cancer Center
state: California
city: Santa Monica
country: United States
facility: UCLA Health - Santa Monica Parkside Cancer Care
state: California
city: Torrance
country: United States
facility: Torrance Memorial Physician Network - Cancer Care and Infusion Center
state: California
city: Whittier
country: United States
facility: PIH Health
state: California
city: Jacksonville
country: United States
facility: Mayo Clinic - Jacksonville
state: Florida
city: Pembroke Pines
country: United States
facility: Memorial Hospital West
state: Florida
city: Grand Rapids
country: United States
facility: Cancer & Hematology Centers of Western Michigan - Lemmen-Holton Cancer Pavilion
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic - Rochester
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine Center for Advanced Medicine
state: Missouri
city: Omaha
country: United States
facility: Nebraska Cancer Specialists - Midwest Cancer Center - Legacy
state: Nebraska
city: Englewood
country: United States
facility: Englewood Health
state: New Jersey
city: Farmington
country: United States
facility: San Juan Oncology Associates
state: New Mexico
city: New York
country: United States
facility: Manhattan Hematology Oncology Associates
state: New York
city: Canton
country: United States
facility: Gabrail Cancer and Research Center
state: Ohio
city: Cincinnati
country: United States
facility: Trihealth Kenwood
state: Ohio
city: Cleveland
country: United States
facility: University Hospitals Cleveland Medical Center
state: Ohio
city: Germantown
country: United States
facility: West Cancer Center - East Campus
state: Tennessee
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center
state: Texas
city: Salt Lake City
country: United States
facility: Utah Cancer Specialists
state: Utah
city: Charlottesville
country: United States
facility: University of Virginia School of Medicine
state: Virginia
city: Fairfax
country: United States
facility: Inova Schar Cancer Institute
state: Virginia
Study officials:
References: