Clinical Trials /

Onvansertib in Combination With FOLFIRI and Bevacizumab for Second Line Treatment of Metastatic Colorectal Cancer Patients With a Kras Mutation

NCT03829410

Description:

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.

Related Conditions:
  • Colorectal Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Onvansertib in Combination With FOLFIRI and Bevacizumab for Second Line Treatment of Metastatic Colorectal Cancer Patients With a Kras Mutation
  • Official Title: A Phase 1b/2 Study of Onvansertib (PCM-075) in Combination With FOLFIRI and Bevacizumab for Second Line Treatment of Metastatic Colorectal Cancer in Patients With a Kras Mutation

Clinical Trial IDs

  • ORG STUDY ID: TROV-054
  • NCT ID: NCT03829410

Conditions

  • Metastatic Colorectal Cancer
  • KRAS Gene Mutation

Interventions

DrugSynonymsArms
OnvansertibOnvansertib + FOLFIRI + Bevacizumab
BevacizumabOnvansertib + FOLFIRI + Bevacizumab
FOLFIRIOnvansertib + FOLFIRI + Bevacizumab

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Onvansertib + FOLFIRI + BevacizumabExperimentalPhase 1b: Onvansertib escalating starting dose of 12 mg/m2 orally Day 1 through 5 every 14-days over two treatment courses (1 cycle) in combination with FOLFIRI (180 mg/m2 irinotecan, 400 g/m2 leucovorin, 400 mg/m2 bolus 5-fluorouracil (5-FU), and 2400 mg/m2 continuous intravenous infusion 5-FU) + 5 mg/kg bevacizumab. Phase 2: Onvansertib Recommended Phase 2 Dose (RP2D) orally Day 1 through 5 every 14-days over two treatment courses (1 cycle) in combination with FOLFIRI (180 mg/m2 irinotecan, 400 g/m2 leucovorin, 400 mg/m2 bolus 5-fluorouracil (5-FU), and 2400 mg/m2 continuous intravenous infusion 5-FU) + 5 mg/kg bevacizumab, with treatment modifications or delays based on unresolved toxicity experienced during a previous cycle.
  • Onvansertib
  • Bevacizumab
  • FOLFIRI

Eligibility Criteria

        Inclusion Criteria:

          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
             without bevacizumab.

        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
        regimen.

        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
        enrollment.

        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.

        Exclusion Criteria:

          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
             randomization.

          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
             resection).

          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
        entry).

        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
        study enrollment.

        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).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase 1: Determine the Maximum Tolerated Dose (MTD)
Time Frame:Baseline up to 28 days after last dose of study drug (up to 30 months)
Safety Issue:
Description:The severity of each AE will be graded using the Common Terminology Criteria for Adverse Events (CTCAE).

Secondary Outcome Measures

Measure:Phase 2: Number of Participants with a Complete Response
Time Frame:Baseline up to 28 days after last dose of study drug (up to 30 months)
Safety Issue:
Description:
Measure:Phase 2: Number of Participants with a Partial Response
Time Frame:Baseline up to 28 days after last dose of study drug (up to 30 months)
Safety Issue:
Description:
Measure:Phase 2: Number of Participants with Stable Disease
Time Frame:Baseline up to 28 days after last dose of study drug (up to 30 months)
Safety Issue:
Description:
Measure:Phase 2: Number of Participants with Progression-free Survival (PFS)
Time Frame:Baseline up to 28 days after last dose of study drug (up to 30 months)
Safety Issue:
Description:Time from first drug administration to progression or death, whichever comes first.
Measure:Phase 2: Number of Participants with a Reduction in Kras Allelic Burden on Liquid Biopsies
Time Frame:Day 1 of each course up to 28 days after last dose of study drug (up to 30 months)
Safety Issue:
Description:Blood samples obtained at baseline and subsequent time points will be analyzed for the presence of circulating tumor DNA (ctDNA [including Kras mutations]).

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Trovagene, Inc.

Trial Keywords

  • Kras mutation
  • PCM-075
  • Onvansertib
  • FOLFIRI
  • Irinotecan
  • 5-Fluorouracil
  • Leucovorin
  • Avastin
  • Bevacizumab

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