Clinical Trials /

Study of XL888 With Vemurafenib for Patients With Unresectable BRAF Mutated Stage III/IV Melanoma

NCT01657591

Description:

This is a multi-cohort, dose-escalation study of XL888 with a fixed dose of vemurafenib. New dose escalation or de-escalation cohorts will be assigned by the Principal Investigator (PI) with discussion with appropriate co-investigators once safety and tolerability is known for a given cohort in accordance to dose escalation rules. Participants will be defined to be enrolled within a cohort upon receipt of first dose of XL888/vemurafenib.

Related Conditions:
  • Melanoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Study of XL888 With Vemurafenib for Patients With Unresectable BRAF Mutated Stage III/IV Melanoma
  • Official Title: Phase I Study of Escalating Doses of XL888 With Vemurafenib for Patients With Unresectable BRAF Mutated Stage III/IV Melanoma

Clinical Trial IDs

  • ORG STUDY ID: MCC-17013
  • NCT ID: NCT01657591

Conditions

  • Melanoma

Interventions

DrugSynonymsArms
XL888molecule inhibitor, Hsp90 inhibitor, EXEL-4888, EXEL-04354888Dose Escalation
VemurafenibZelboraf ®, PLX-4032, RG 7204, RO5185426Dose Escalation

Purpose

This is a multi-cohort, dose-escalation study of XL888 with a fixed dose of vemurafenib. New dose escalation or de-escalation cohorts will be assigned by the Principal Investigator (PI) with discussion with appropriate co-investigators once safety and tolerability is known for a given cohort in accordance to dose escalation rules. Participants will be defined to be enrolled within a cohort upon receipt of first dose of XL888/vemurafenib.

Detailed Description

      In this study, the investigational drug XL888 will be given along with the drug vemurafenib.
      The investigators want to learn more about the safety and side effects of XL888 and hope to
      find out what dose of the drug can be given safely without serious side effects. Based on
      research done in a laboratory on tissue samples (cells collected from living things), the
      researchers think that XL888 might help to make vemurafenib work to fight cancer cells in the
      body for a longer period of time.
    

Trial Arms

NameTypeDescriptionInterventions
Dose EscalationExperimentalThe treatment period will include dosing (taking a certain amount on a regular schedule) with vemurafenib along with the study drug, XL888. Everyone in the study will receive both drugs, but the XL888 will be given at different doses (different amounts). Everyone in this study will be given vemurafenib at the standard dose (the amount of the drug that is given as standard treatment) of 960 milligrams (mg) twice per day, unless the first people in the study have severe side effects when taking the lowest dose of XL888 along with vemurafenib. If that happens, the next people in the study may be given a lower dose of vemurafenib (720 mg twice per day) along with the lowest dose of XL888.
  • XL888
  • Vemurafenib

Eligibility Criteria

        Inclusion Criteria:

          -  Must have cytologically or histologically-confirmed unresectable melanoma that harbors
             a BRAF V600 E or K mutation determined by pyrosequencing assay or equivalent
             genotyping assay in a Clinical Laboratory Improvement Amendments (CLIA) certified
             laboratory, meeting one of the following American Joint Committee on Cancer (AJCC)
             staging criteria:

               -  AJCC Stage IV (Tany, Nany, M1a, b, or c)

               -  AJCC Stage III B or C with unresectable nodal/locoregional involvement

          -  Adequate hepatic, renal, and bone marrow function as defined by the following
             parameters obtained within 2 weeks prior to initiation of study treatment:

               -  Hematologic Criteria: leukocytes ≥3,000/mcL; absolute neutrophil count
                  ≥1,500/mcL; platelets ≥100,000/mcL

               -  Renal Criteria: serum creatinine within normal institutional limits or a
                  creatinine clearance ≥60 mL/min for patients with creatinine levels above
                  institutional normal

               -  Hepatic Criteria: aspartate aminotransferase (AST)/alanine transaminase (ALT)
                  ≤2.5 X institutional upper limit of normal; if liver metastasis present, then
                  AST/ALT may be less than or equal to 5 times the upper limit of normal

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

          -  Willing to give written informed consent per institutional guidelines and must be able
             to adhere to dose and visit schedules

          -  Female and male participants must agree to use a medically acceptable method of birth
             control prior to screening and agree to continue its use throughout the study. Females
             of childbearing potential should be counseled in the appropriate use of birth control
             while on this study.

          -  Treatment-naïve and previously treated patients will be included; however, patients
             may not have received a BRAF or HSP90 inhibitor in the past.

          -  Patients must be at least 4 weeks from any prior systemic therapy (6 weeks for
             nitrosoureas or mitomycin C), surgery or radiation.

          -  Must have measurable disease as defined by RECIST 1.1

        Exclusion Criteria:

          -  Females who are pregnant, intend to become pregnant or are nursing. Females with
             child-bearing potential must have a negative pregnancy test within one week of
             enrollment.

          -  Previously treated with BRAF or HSP90 inhibitor therapy

          -  Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
             nitrosoureas or mitomycin C) prior to entering the study or those who have not
             recovered from adverse events due to agents administered more than 4 weeks earlier.

          -  Patients who are receiving any other investigational agents.

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition (i.e. ethanol) to XL888 or vemurafenib (i.e., ethanol).

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris,
             uncontrolled or symptomatic cardiac arrhythmia, or psychiatric illness/social
             situations that would limit compliance with study requirements

          -  HIV-positive patients on combination antiretroviral therapy are ineligible because of
             the potential for pharmacokinetic interactions with XL888 and vemurafenib.

          -  Untreated or uncontrolled brain metastases or evidence of leptomeningeal disease.
             Brain metastases that have been appropriately treated with radiation and/or surgery
             will be allowed as long as the central nervous system (CNS) disease has been stable
             for at least 4 weeks post-treatment.

          -  Must be at least 3 years from any prior malignancy and have no evidence of the
             malignancy at the time of enrollment. Patients with adequately treated squamous cell
             or basal cell carcinomas of the skin, multiple primary melanomas, or any carcinoma in
             situ will be allowed.

          -  Corrected QT interval (QTc) greater than 460 ms at baseline
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose (MTD) and Recommended Phase II Dose (RP2D)
Time Frame:Average of 36 weeks
Safety Issue:
Description:MTD and RP2D of XL888 when administered orally with vemurafenib to patients with BRAF V600 mutated melanoma, and evaluate the safety and tolerability of this combination. Safety will be assessed by evaluation of adverse events (AEs), vital signs, electrocardiogram (ECG), laboratory tests and concomitant medications. Adverse event terms recorded on the case report forms (CRFs) will be standardized using the Medical Dictionary for Regulatory Activities (MedDRA). Severity grade will be defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Summaries will be directed toward treatment-emergent adverse events (TEAEs), defined as events that start or worsen after the first dose of study treatment. TEAEs will be tabulated in accordance with system organ class and preferred term by overall incidence, worst reported severity, and relationship to study treatment.

Secondary Outcome Measures

Measure:Progression Free Survival (PFS) Rate
Time Frame:6 months
Safety Issue:
Description:Progression Free Survival at 6 months. The median time and its 95% confidence intervals will be estimated using the Kaplan-Meier method for the same cohort. The corresponding Kaplan-Meier curves will also be generated.
Measure:Overall Survival (OS) Rate
Time Frame:1 year
Safety Issue:
Description:Overall Survival at 1 year. The median time and its 95% confidence intervals will be estimated using the Kaplan-Meier method for the same cohort. The corresponding Kaplan-Meier curves will also be generated.
Measure:Best Overall Response Rate (ORR)
Time Frame:18 months
Safety Issue:
Description:The best overall response is the best response recorded from the start of the treatment until the end of treatment taking into account any requirement for confirmation. In general, the patient's best response assignment will depend on findings of both target and non-target disease and will also take into consideration the appearance of new lesions. Tumor response for all participants will be assessed using the Response Evaluation Criteria in Solid Tumors (RECIST, V1.1).

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:H. Lee Moffitt Cancer Center and Research Institute

Trial Keywords

  • skin cancer
  • unresectable
  • BRAF

Last Updated

December 4, 2020