A Trial of Single Agent Axitinib as Maintenance Therapy for Patients With First Line Metastatic Colorectal Cancer (mCRC)

• ClinicalTrials.gov Identifier: NCT01490866
• Recruitment Status: Completed
• First Posted: December 13, 2011
• Results First Posted: January 12, 2017
• Last Update Posted: September 24, 2019
• Sponsor: SCRI Development Innovations, LLC
• Collaborator: Pfizer
• Information provided by (Responsible Party): SCRI Development Innovations, LLC

Tracking Information

• First Submitted Date: November 7, 2011
• First Posted Date: December 13, 2011
• Results First Submitted Date: September 21, 2016
• Results First Posted Date: January 12, 2017
• Last Update Posted Date: September 24, 2019
• Study Start Date: January 2012
• Actual Primary Completion Date: July 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 15, 2016)

Progression-free Survival [ Time Frame: 24 months ]

Defined as the time from first treatment until objective tumor progression or death from any cause, assessed according to Response Evaluation Criteria for Solid Tumors (RECIST) v1.1.

Original Primary Outcome Measures (submitted: December 12, 2011)

Progression-free survival (PFS) [ Time Frame: 18 months ]

Determine the PFS of patients with first-line mCRC treated with maintenance axitinib after initial treatment with FOLFOX plus bevacizumab.

Current Secondary Outcome Measures (submitted: November 15, 2016)

• Objective Response Rate [ Time Frame: every 8 weeks, assessed up to approximately 24 months ]
  Defined as the percentage of evaluable patients showing a complete or partial response (CR or PR) per RECIST v1.1 criteria. CR = disappearance of all lesions. PR = at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. Stable disease (SD) = neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest (nadir) sum LD since start of treatment.
• Time To Progression (TTP) [ Time Frame: every 8 weeks, assessed approximately up to 24 months ]
  Defined as the time after a disease is diagnosed (or treated) until worsening of the disease.
• Overall Survival (OS) [ Time Frame: every 8 weeks until progression then every 3 months for up to 5 years. ]
  Defined as the time from first treatment until death from any cause.
• Frequency of Adverse Events as a Measure of Safety [ Time Frame: Every 4 weeks plus 30 days during treatment and up to 5 years thereafter. ]
  The frequency of adverse events (AEs) was analyzed in 2 groups of patients, those receiving FOLFOX/bevacizumab (N=70), and patients who received axitinib maintenance (N = 48). AEs were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0.

Original Secondary Outcome Measures (submitted: December 12, 2011)

• Objective Response Rate (ORR) [ Time Frame: 18 months ]
  Determine the Response Rate of patients with first-line mCRC treated with maintenance axitinib after initial treatment with FOLFOX plus bevacizumab.
• Toxicities [ Time Frame: 18 months ]
  Abnormal Thyroid Function - Serum or plasma thyroid function tests; Gastrointestinal Disorders - Supportive care for these events may include pre-medication with anti-emetics; Hematological and Urinary Disorders - Urine dipstick test; Hypertension - Measurements of BP
• Time To Progression (TTP) [ Time Frame: 18 months ]
  Determine Time To Progression of patients with first-line mCRC treated with maintenance axitinib after initial treatment with FOLFOX plus bevacizumab.
• Overall Survival (OS) [ Time Frame: 18 months ]
  Determine Overal Survival (OS) of patients with first-line mCRC treated with maintenance axitinib after intial treatment with FOLFOX plus bevacizumab.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Trial of Single Agent Axitinib as Maintenance Therapy for Patients With First Line Metastatic Colorectal Cancer (mCRC)
• Official Title: A Phase II Trial of Single Agent Axitinib as Maintenance Therapy for Patients With First Line Metastatic Colorectal Cancer (mCRC)
• Brief Summary: This is a non-randomized, open-label, Phase II trial investigating axitinib as a single-agent maintenance therapy following standard first-line FOLFOX/bevacizumab therapy for patients with mCRC.
• Detailed Description: All patients will receive FOLFOX/bevacizumab for four 28-day cycles (a total of 16 weeks). After 4 cycles, maintenance axitinib will be started. With approval of the Medical Monitor,patients who are having significant benefit from FOLFOX/bevacizumab may continue chemotherapy to a maximum of six 28-day cycles. During trial treatment, all patients will be assessed for response every 8 weeks (2 cycles).
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Colorectal Cancer

Intervention

• Drug: Axitinib
  5-mg tablets PO BID
  Other Name: AG-013736
• Drug: Bevacizumab
  5 mg/kg Days 1 and 15; IV
  Other Name: Avastin
• Drug: 5-Fluorouracil
  400 mg/m2 Days 1 and 15; IV
  Other Name: 5-FU
• Drug: 5-Fluorouracil
  2400 mg/m2 over 46-48 hours Days 1 and 15; Continuous Intravenous
  Other Name: 5-FU
• Drug: Leucovorin
  400 mg/m2 Days 1 and 15; IV
  Other Name: folinic acid
• Drug: Oxaliplatin
  85 mg/m2 Days 1 and 15; IV
  Other Name: Eloxatin

Study Arms

Experimental: FOLFOX/bevacizumab and Axitinib

Phase II trial investigating axitinib as a single-agent maintenance therapy following standard first-line FOLFOX/bevacizumab therapy for patients with mCRC. (FOLFOX is a combination of 5-Fluorouracil, Leucovorin and Oxaliplatin.)

All patients will receive FOLFOX/bevacizumab for four 28-day cycles (a total of 16 weeks). After 4 cycles, maintenance axitinib will be started.

Interventions:

• Drug: Axitinib
• Drug: Bevacizumab
• Drug: 5-Fluorouracil
• Drug: 5-Fluorouracil
• Drug: Leucovorin
• Drug: Oxaliplatin

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: January 23, 2015): 70
• Original Estimated Enrollment (submitted: December 12, 2011): 69
• Actual Study Completion Date: July 2015
• Actual Primary Completion Date: July 2015 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Histologically or cytologically confirmed metastatic adenocarcinoma of the colon or rectum.
• Patients must have measurable disease per RECIST Version 1.1.
• No previous systemic therapy for metastatic colorectal cancer. Previous radiosensitizing chemotherapy is allowed, if completed at least 4 weeks prior to Cycle 1 Day 1 of study treatment, and previous neoadjuvant and/or adjuvant chemotherapy is allowed, if completed at least 6 months prior to diagnosis of metastatic disease.
• Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 to 1.
• Life expectancy >=12 weeks.
• Adequate hematologic, renal and hepatic function
• Patients who are on coumadin should have an INR value within the therapeutic range (i.e., 2 to 3 x ULN). Patients who are on stable, chronic doses of coumadin are eligible.
• Male patients willing to use adequate contraceptive measures. Female patients who are not of child-bearing potential, and female patients of child-bearing potential who agree to use adequate contraceptive measures, who are not breastfeeding, and who have a negative serum or urine pregnancy test performed within 72 hours prior to start of treatment.
• Willingness and ability to comply with the trial and follow-up procedures.
• Ability to understand the investigative nature of this trial and give written informed consent.

Exclusion Criteria:

• History or known presence of central nervous system (CNS) metastases.
• Patients who have had a major surgical procedure (not including mediastinoscopy), or significant traumatic injury <=4 weeks prior to beginning treatment.
• Women who are pregnant or lactating. All females of child-bearing potential must have negative serum or urine pregnancy tests within 72 hours prior to study treatment (see Appendix D)
• History of hypersensitivity to active or inactive excipients of any component of treatment (5 fluorouracil, bevacizumab, oxaliplatin, or axitinib), or known dipyrimidine dehydrogenase deficiency.

• Patients with proteinuria at screening as demonstrated by:

  • Urine dipstick for 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/24 hours to be eligible)
• Patients with a serious non healing wound, active ulcer, or untreated bone fracture.
• Patients with evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation).
• Patients with history of hematemesis or hemoptysis (defined as having bright red blood of ½ teaspoon or more per episode) <=1 month prior to study enrollment.
• Patients requiring concomitant treatment with potent CYP3A4 or CYP1A2 inducers and CYP3A4 inhibitors.
• History of myocardial infarction or unstable angina <=6 months prior to beginning treatment.
• Inadequately controlled hypertension (defined as systolic blood pressure >150 mmHg and/or diastolic blood pressure >100 mmHg while on antihypertensive medications). Initiation of antihypertensive agents is permitted provided adequate control is documented at least 1 week prior to Day 1 of study treatment.
• New York Heart Association Grade II or greater congestive heart failure.
• Serious cardiac arrhythmia requiring medication. Patients with chronic, rate-controlled atrial fibrillation are eligible.
• Significant vascular disease (e.g., aortic aneurysm requiring surgical repair, or recent peripheral arterial thrombosis) <=6 months prior to Day 1 of treatment.
• History of stroke or transient ischemic attack <=6 months prior to beginning treatment.
• Any prior history of hypertensive crisis or hypertensive encephalopathy.
• History of abdominal fistula or gastrointestinal perforation <=6 months prior to Day 1 of beginning treatment.
• Concurrent severe, intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements.
• Any known positive test for human immunodeficiency virus, hepatitis C virus or acute or chronic hepatitis B infection.
• Mental condition that would prevent patient comprehension of the nature of, and risk associated with, the study.
• Use of any non-approved or investigational agent <=28 days prior to administration of the first dose of study drug. Patients may not receive any other investigational or anti-cancer treatments while participating in this study.
• Past or current history of neoplasm other than the entry diagnosis with the exception of treated non-melanoma skin cancer or carcinoma in situ of the cervix, or other cancers cured by local therapy alone and a disease free survival >=5 years.
• Infection requiring IV antibiotics.
• Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter drug absorption (e.g. active inflammatory bowel disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or significant small bowel resection).
• Inability to swallow whole tablets.
• Patients with > Grade 2 peripheral neuropathy.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01490866
• Other Study ID Numbers: SCRI GI 154
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: SCRI Development Innovations, LLC
• Study Sponsor: SCRI Development Innovations, LLC
• Collaborators: Pfizer

Investigators

• Study Chair: Johanna Bendell, M.D.; SCRI Development Innovations, LLC

• PRS Account: SCRI Development Innovations, LLC
• Verification Date: September 2019