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

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ClinicalTrials.gov Identifier: NCT03829410
Recruitment Status : Recruiting
First Posted : February 4, 2019
Last Update Posted : June 24, 2019
Sponsor:
Information provided by (Responsible Party):
Trovagene, Inc.

Tracking Information
First Submitted Date  ICMJE February 1, 2019
First Posted Date  ICMJE February 4, 2019
Last Update Posted Date June 24, 2019
Actual Study Start Date  ICMJE May 6, 2019
Estimated Primary Completion Date May 25, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 1, 2019)
  • 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) ]
  • Phase 1: Number of Participants With Adverse Events (AEs) [ Time Frame: Baseline up to 28 days after last dose of study drug (up to 30 months) ]
    The severity of each AE will be graded using the Common Terminology Criteria for Adverse Events (CTCAE).
  • Phase 1: Number of Participants with Clinically Significant Change From Baseline in Vital Signs [ Time Frame: Baseline up to 28 days after last dose of study drug (up to 30 months) ]
  • Phase 1: Number of Participants With Clinically Significant Change From Baseline in Laboratory Parameters [ Time Frame: Baseline up to 28 days after last dose of study drug (up to 30 months) ]
  • Phase 1: Number of Participants With Clinically Significant Change from Baseline in Electrocardiograms (ECG) [ Time Frame: Baseline up to 28 days after last dose of study drug (up to 30 months) ]
  • Phase 1: Number of Participants with Clinically Significant Physical Examination Findings [ Time Frame: Baseline up to 28 days after last dose of study drug (up to 30 months) ]
  • Phase 1: Number of Participants With Clinically Significant Change From Baseline in Body Weight [ Time Frame: Baseline up to 28 days after last dose of study drug (up to 30 months) ]
  • Phase 1: Number of Participants With Change from Baseline in Eastern Co-operative Oncology Group (ECOG) Performance Status [ Time Frame: Baseline up to 28 days after last dose of study drug (up to 30 months) ]
    ECOG performance measured on-therapy.
  • Phase 2: Number of Participants with an Objective Response Rate (ORR) [ Time Frame: Baseline up to 28 days after last dose of study drug (up to 30 months) ]
    The ORR is determined by Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) in patients who receive at least 1 cycle (2 courses) of onvansertib in combination with FOLFIRI and bevacizumab. The response rate calculates the percentage of participants having a complete response or partial response during treatment.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03829410 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: February 1, 2019)
  • 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) ]
  • 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) ]
  • 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) ]
  • 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) ]
    Time from first drug administration to progression or death, whichever comes first.
  • 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) ]
    Blood samples obtained at baseline and subsequent time points will be analyzed for the presence of circulating tumor DNA (ctDNA [including Kras mutations]).
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Onvansertib in Combination With FOLFIRI and Bevacizumab for Second Line Treatment of Metastatic Colorectal Cancer Patients With a Kras Mutation
Official Title  ICMJE 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
Brief Summary 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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Metastatic Colorectal Cancer
  • KRAS Gene Mutation
Intervention  ICMJE
  • Drug: Onvansertib
    Onvansertib orally.
  • Biological: Bevacizumab
    Bevacizumab intravenously.
  • Drug: FOLFIRI
    FOLFIRI intravenously.
Study Arms  ICMJE Experimental: Onvansertib + FOLFIRI + Bevacizumab

Phase 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.

Interventions:
  • Drug: Onvansertib
  • Biological: Bevacizumab
  • Drug: FOLFIRI
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: February 1, 2019)
44
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE May 25, 2021
Estimated Primary Completion Date May 25, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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).

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Central Contact Lead 858-952-7652 VKelemen@trovagene.com
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03829410
Other Study ID Numbers  ICMJE TROV-054
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Trovagene, Inc.
Study Sponsor  ICMJE Trovagene, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Trovagene, Inc.
Verification Date June 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP