Safety, Tolerability, and Pharmacokinetics of Onartuzumab Combined With Vemurafenib and/or Cobimetinib in Cancer Patients

• ClinicalTrials.gov Identifier: NCT01974258
• Recruitment Status: Withdrawn
• First Posted: November 1, 2013
• Last Update Posted: November 2, 2016
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

Tracking Information

• First Submitted Date: October 28, 2013
• First Posted Date: November 1, 2013
• Last Update Posted Date: November 2, 2016
• Study Start Date: February 2014
• Estimated Primary Completion Date: July 2014 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 28, 2013)

• Safety: Incidence of dose-limiting toxicities (DLTs) of vermurafenib and/or cobimetinib used in combination with onartuzumab. [ Time Frame: 24 to 36 months ]
• Safety: Incidence of anti-therapeutic antibodies against onartuzumab. [ Time Frame: 24 to 36 months ]
• Safety: Incidence of adverse events (AE) [ Time Frame: 24 to 36 months ]

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: October 28, 2013)

• Pharmacokinetics: Maximum concentration (Cmax) of onartuzumab [ Time Frame: 24 to 36 months ]
• Pharmacokinetics: Maximum concentration (Cmax) of cobimetinib [ Time Frame: 24 to 36 months ]
• Pharmacokinetics: Maximum concentration (Cmax) of vemurafenib [ Time Frame: 24 to 36 months ]
• Efficacy: Overall response rate [ Time Frame: 24 to 36 months ]
• Efficacy: Progression-free survival [ Time Frame: 24 to 36 months ]
• Efficacy: Duration of response [ Time Frame: 24 to 36 months ]
• Efficacy: Overall survival [ Time Frame: 24 to 36 months ]

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Safety, Tolerability, and Pharmacokinetics of Onartuzumab Combined With Vemurafenib and/or Cobimetinib in Cancer Patients
• Official Title: A PHASE Ib, OPEN-LABEL STUDY EVALUATING THE SAFETY, TOLERABILITY, AND PHARMACOKINETICS OF ONARTUZUMAB IN COMBINATION WITH VEMURAFENIB AND/OR COBIMETINIB IN PATIENTS WITH ADVANCED SOLID MALIGNANCIES
• Brief Summary: This study will evaluate the maximum tolerated dose and dose-limiting toxicities of vemurafenib and/or cobimetinib when used with onartuzumab in cancer patients.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Neoplasms

Intervention

• Drug: Cobimetinib
  Escalating dose
• Drug: Cobimetinib
  Orally administered once daily for 21 consecutive days, followed by 7 days off.
• Drug: Onartuzumab
  Administered by IV infusion every 2 weeks
• Drug: Vemurafenib
  Orally administered twice daily

Study Arms

• Experimental: Dose-expansion: onartuzumab + cobimetinib
  Interventions:

  • Drug: Cobimetinib
  • Drug: Onartuzumab
• Experimental: Dose-expansion: onartuzumab + vemurafenib
  Interventions:

  • Drug: Onartuzumab
  • Drug: Vemurafenib
• Experimental: Dose-expansion: onartuzumab + vemurafenib + cobimetinib
  Interventions:

  • Drug: Cobimetinib
  • Drug: Onartuzumab
  • Drug: Vemurafenib
• Experimental: Dose-finding: onartuzumab + vemurafenib + cobimetinib
  Interventions:

  • Drug: Cobimetinib
  • Drug: Onartuzumab
  • Drug: Vemurafenib

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Withdrawn
• Actual Enrollment (submitted: August 1, 2016): 0
• Original Estimated Enrollment (submitted: October 28, 2013): 96
• Estimated Study Completion Date: July 2014
• Estimated Primary Completion Date: July 2014 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Adult patients >/= 18 years of age.
• Patients with histologically confirmed, BRAFV600-mutant, unresectable, locally advanced or metastatic solid malignancies. OR
• Patients with a histologically confirmed, KRAS-mutant, Stage IV colorectal adenocarcinoma, or KRAS-mutant metastatic non-small-cell lung carcinoma. OR
• Patients with histologically confirmed BRAFV600-mutant unresectable Stage IIIC or Stage IV metastatic melanoma.
• Valid MET IHC test result.
• Measurable disease per Response Evaluation Criteria in Solid Tumors v1.1
• ECOG performance status of 0 or 1.
• For BRAFV600-mutant cancers:
• Previously untreated for their melanoma or previously treated for their melanoma but without prior exposure to any HGF, MET, BRAF, or MEK inhibitor therapy
• BRAFV600-mutant solid malignancies other than melanoma for which standard therapy does not exist has proven to be ineffective or intolerable or is considered inappropriate.

Patients must not have had prior exposure to HGF, MET, BRAF, or MEK inhibitor therapy.

• For KRAS-mutant cancers:
• mCRC patients must have received therapeutic regimens including oxaliplatin, irinotecan, 5-FU, and bevacizumab, or determined to be ineligible for these treatments. Patients must not have had prior exposure to HGF, MET, BRAF, or MEK inhibitor therapy.
• Metastatic NSCLC patients must have received platinum-based doublet chemotherapy or determined to be ineligible for this regimen. Patients must not have had prior exposure to HGF, MET, BRAF, or MEK inhibitor therapy.
• Consent to provide tumor tissue for biomarker analyses.
• Life expectancy >/= 12 weeks.
• Fully recovery from the effects of any major surgery or significant traumatic injury within 14 days from the first dose of study treatment.
• Adequate hematologic and end organ function, as defined by clinical laboratory results.
• Use of effective form(s) of contraception as defined by protocol during the course of this study and for at least 6 months after study drug discontinuation.

Exclusion Criteria:

• Palliative radiotherapy or experimental therapy within 28 days prior to first dose of study drug treatment.
• Major surgical procedure or significant traumatic injury from 28 days prior to first dose of study drug treatment until end of study.
• History of another malignancy in the previous 5 years, unless cured by surgery alone and continuously disease free. Exceptions include appropriately treated cervical carcinoma in situ, non-melanoma skin carcinoma, Stage I uterine cancer, localized prostate cancer that has been treated surgically and is presumed cured, or other malignancies with an expected curative outcome.
• Brain metastasis or spinal cord compression not definitively treated with surgery and/or radiation, or previously diagnosed and treated central nervous system (CNS) metastases or spinal cord compression without evidence of clinically stable disease for more than 14 days.

Note: Patients with treated CNS metastases who are asymptomatic and on a stable dose of corticosteroids for more than 14 days prior to Cycle 1 Day 1 are eligible.

• For patients given cobimetinib: Evidence of visible retinal pathology that is considered a risk factor for neurosensory detachment, retinal vein occlusion, or neovascular macular degeneration, or of conditions that are risk factors for retinal vein occlusion.
• Current or history of clinically significant cardiac or pulmonary dysfunction.
• Lack of recovery to Grade 1 or better from adverse events due to investigational or other agents administered more than 28 days prior to enrollment, except for alopecia.
• Current severe, uncontrolled systemic disease.
• Inability or unwillingness to swallow pills.
• History of malabsorption or other condition that would interfere with gastrointestinal absorption of study drug.
• History of clinically significant liver disease, current alcohol abuse, or known infection with HIV, hepatitis B virus (HBV), or hepatitis C virus (HCV).
• Severe (Grade 3 and above) active infection at enrollment, or other serious underlying medical conditions.
• Required medication known to cause edema and/or cardiac failure.
• Active autoimmune disease.
• Uncontrolled ascites requiring weekly, large-volume paracentesis for 3 consecutive weeks prior to enrollment.

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: NCT01974258
• Other Study ID Numbers: GO29026
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Hoffmann-La Roche
• Original Responsible Party: Same as current
• Current Study Sponsor: Hoffmann-La Roche
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Clinical Trials; Hoffmann-La Roche

• PRS Account: Hoffmann-La Roche
• Verification Date: November 2016