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

This study is currently recruiting participants.
Verified April 2014 by H. Lee Moffitt Cancer Center and Research Institute
Sponsor:
Collaborator:
Exelixis
Information provided by (Responsible Party):
H. Lee Moffitt Cancer Center and Research Institute
ClinicalTrials.gov Identifier:
NCT01657591
First received: August 2, 2012
Last updated: April 15, 2014
Last verified: April 2014
  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.


Condition Intervention Phase
Melanoma
Drug: XL888
Drug: Vemurafenib
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I Study of Escalating Doses of XL888 With Vemurafenib for Patients With Unresectable BRAF Mutated Stage III/IV Melanoma

Resource links provided by NLM:


Further study details as provided by H. Lee Moffitt Cancer Center and Research Institute:

Primary Outcome Measures:
  • Maximum Tolerated Dose (MTD) and Recommended Phase II Dose (RP2D) [ Time Frame: Average of 36 weeks ] [ Designated as safety issue: Yes ]
    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:
  • Progression Free Survival (PFS) Rate [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    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.

  • Overall Survival (OS) Rate [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    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.

  • Overall Response Rate (ORR) [ Time Frame: 18 months ] [ Designated as safety issue: No ]
    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).


Estimated Enrollment: 36
Study Start Date: July 2012
Estimated Study Completion Date: January 2015
Estimated Primary Completion Date: January 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Dose Escalation
The 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.
Drug: XL888
Level -1: XL888 30 mg; Level 1: XL888 30 mg; Level 2: XL888 45 mg; Level 3: XL888 90 mg; Level 4: XL888 135 mg
Other Names:
  • molecule inhibitor
  • Hsp90 inhibitor
  • EXEL-4888
  • EXEL-04354888
Drug: Vemurafenib
Level -1: Vemurafenib 720 mg; Level 1: Vemurafenib 960 mg; Level 2: Vemurafenib 960 mg; Level 3: Vemurafenib 960 mg; Level 4: Vemurafenib 960 mg
Other Names:
  • Zelobraf ®
  • PLX-4032
  • RG 7204
  • RO5185426

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Must have cytologically or histologically-confirmed unresectable melanoma that harbors a BRAF V600 E or K mutation determined by pyrosequencing assay, 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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01657591

Locations
United States, Florida
H. Lee Moffitt Cancer Center and Research Institute Recruiting
Tampa, Florida, United States, 33612
Contact: Leticia Tetteh    813-745-4617    leticia.tetteh@moffitt.org   
Principal Investigator: Geoffrey Gibney, M.D.         
Sub-Investigator: Jeffrey Weber, M.D., Ph.D.         
Sub-Investigator: Timothy McCardle, M.D.         
Sub-Investigator: Jane Messina, M.D.         
Sub-Investigator: Amod Sarnaik, M.D.         
Sub-Investigator: Keiran Smalley, Ph.D.         
Sub-Investigator: Jonathan Zager, M.D.         
Sub-Investigator: Vernon Sondak, M.D.         
Sponsors and Collaborators
H. Lee Moffitt Cancer Center and Research Institute
Exelixis
Investigators
Principal Investigator: Geoffrey Gibney, M.D. H. Lee Moffitt Cancer Center and Research Institute
  More Information

Additional Information:
No publications provided

Responsible Party: H. Lee Moffitt Cancer Center and Research Institute
ClinicalTrials.gov Identifier: NCT01657591     History of Changes
Other Study ID Numbers: MCC-17013
Study First Received: August 2, 2012
Last Updated: April 15, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by H. Lee Moffitt Cancer Center and Research Institute:
skin cancer
unresectable
BRAF

Additional relevant MeSH terms:
Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas

ClinicalTrials.gov processed this record on April 17, 2014