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XL888 + Vemurafenib + Cobimetinib for Unresectable BRAF Mutated Stage III/IV Melanoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02721459
Recruitment Status : Active, not recruiting
First Posted : March 29, 2016
Last Update Posted : February 27, 2023
Genentech, Inc.
Information provided by (Responsible Party):
H. Lee Moffitt Cancer Center and Research Institute

Brief Summary:
The main purpose of this study is to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of XL888 when administered orally with vemurafenib plus cobimetinib in participants with BRAF V600 mutated melanoma and to evaluate the safety and tolerability of this combination.

Condition or disease Intervention/treatment Phase
Melanoma Skin Cancer Drug: XL888 Drug: Vemurafenib Drug: Cobimetinib Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 26 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Study of Escalating Doses of XL888 With Vemurafenib Plus Cobimetinib for Patients With Unresectable BRAF Mutated Stage III/IV Melanoma
Actual Study Start Date : August 11, 2016
Actual Primary Completion Date : October 31, 2019
Estimated Study Completion Date : October 2023

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Melanoma
MedlinePlus related topics: Melanoma

Arm Intervention/treatment
Experimental: Dose Escalation
Escalating Doses of XL888 with Vemurafenib plus Cobimetinib.
Drug: XL888

Level 1: XL888 30 mg by mouth (PO) twice weekly (BIW). Level 2: XL888 45 mg PO BIW.

Level 3: XL888 60 mg PO BIW. Level 4: XL888 90 mg PO BIW.

Other Name: HSP90 inhibitor

Drug: Vemurafenib
Vemurafenib 720 mg by mouth twice a day (BID)
Other Name: Zelboraf ®

Drug: Cobimetinib
Cobimetinib 40 mg by mouth once daily (QD). Administered 3 weeks on, 1 week off.
Other Name: GDC-0973/XL518

Primary Outcome Measures :
  1. Maximum Tolerated Dose (MTD) [ Time Frame: Up to 12 months ]
    The maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of XL888 when administered orally with vemurafenib plus cobimetinib in patients with BRAF V600 mutated melanoma.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Must be 18 years of age or above. All races and ethnicities are eligible and no upper limit of age is specified.
  • Must have cytologically or histologically-confirmed unresectable melanoma that harbors a BRAF V600 mutation determined by pyrosequencing assay or equivalent genotyping assay in a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory, meeting one of the following AJCC staging criteria: 1.) American Joint Committee on Cancer (AJCC) stage IV (Tany, Nany, M1a, b, or c); 2.) AJCC stage IIIB or IIIC with unresectable nodal/locoregional involvement.
  • Adequate hepatic, renal, and bone marrow function with parameters obtained within 4 weeks prior to initiation of study treatment.
  • Eastern Cooperative Oncology Group (ECOG) performance status of ≤2.
  • Willing to give written informed consent per institutional guidelines and must be able to adhere to dose and visit schedules.
  • Negative serum pregnancy test within 7 days prior to commencement of dosing in premenopausal women. Women of non-childbearing potential may be included without serum pregnancy test if they are either surgically sterile or have been postmenopausal for ≥1 year.
  • Fertile men and women must use an effective method of contraception during treatment and for at least 6 months after completion of treatment as directed by their physician.
  • Treatment-naïve and previously treated patients will be included; however, patients may not have received a BRAF, Mitogen Activated Kinase (MEK) or HSP90 inhibitor in the past.
  • May have received prior systemic and/or radiation therapy. All adverse events associated with prior systemic therapy or radiation therapy must have resolved to ≤ Grade 1 prior to start of study.
  • Must have measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

Exclusion Criteria:

  • Women who are pregnant, intend to become pregnant or are nursing.
  • Previously treated with BRAF, MEK or HSP90 inhibitor therapy.
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements.
  • HIV-positive patients on combination antiretroviral therapy.
  • Potential participants with untreated or uncontrolled brain metastases or evidence of leptomeningeal disease. Patients with asymptomatic brain metastases or previously treated brain metastases that are stable (i.e., not requiring corticosteroids) at the time of study start will be eligible.
  • Previous malignancy is not an exclusion provided that the other malignancy is considered under control, patient is not on concomitant anti-cancer drug therapy, and target lesions from melanoma are clearly defined for response assessment.
  • History of malabsorption or other condition that would interfere with absorption of study drugs.
  • The following foods/supplements are prohibited at least 7 days prior to initiation of and during study treatment: St. John's wort or hyperforin (potent cytochrome P450 CYP3A4 enzyme inducer); Grapefruit juice (potent cytochrome P450 CYP3A4 enzyme inhibitor).
  • Ocular: History of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment, retinal vein occlusion (RVO), or neovascular macular degeneration.
  • Cardiac: History of clinically significant cardiac dysfunction.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02721459

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United States, Florida
H. Lee Moffitt Cancer Center and Research Institute
Tampa, Florida, United States, 33612
Sponsors and Collaborators
H. Lee Moffitt Cancer Center and Research Institute
Genentech, Inc.
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Principal Investigator: Zeynep Eroglu, M.D. H. Lee Moffitt Cancer Center and Research Institute
Additional Information:
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Responsible Party: H. Lee Moffitt Cancer Center and Research Institute Identifier: NCT02721459    
Other Study ID Numbers: MCC-18597
First Posted: March 29, 2016    Key Record Dates
Last Update Posted: February 27, 2023
Last Verified: February 2023

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by H. Lee Moffitt Cancer Center and Research Institute:
unresectable melanoma
stage III melanoma
stage IV melanoma
AJCC melanoma staging
American Joint Committee on Cancer (AJCC)
BRAF V600 E mutation
BRAF V600 K mutation
Additional relevant MeSH terms:
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Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Nerve Tissue
Nevi and Melanomas
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action