Now Available for Public Comment: Notice of Proposed Rulemaking (NPRM) for FDAAA 801 and NIH Draft Reporting Policy for NIH-Funded Trials

BKM120 Combined With Vemurafenib (PLX4032) in BRAFV600E/K Mutant Advanced Melanoma

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2013 by University of California, San Francisco
Sponsor:
Collaborator:
Novartis
Information provided by (Responsible Party):
Alain Algazi, University of California, San Francisco
ClinicalTrials.gov Identifier:
NCT01512251
First received: December 20, 2011
Last updated: May 20, 2013
Last verified: May 2013
  Purpose

This is a phase 1/2 clinical trial with the goal of determining whether the addition of the investigational agent BKM120 to vemurafenib will lead to improved 6-month progression-free survival in patients with BRAFV600E/K mutant melanoma.


Condition Intervention Phase
BRAF Mutant Metastatic Melanoma
Drug: BKM120 Combined with Vemurafenib (PLX4032)
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 1/2 Trial of BKM120 Combined With Vemurafenib (PLX4032) in BRAFV600E/K Mutant Advanced Melanoma (Novartis Study Number CBKM120ZUS21T)

Resource links provided by NLM:


Further study details as provided by University of California, San Francisco:

Primary Outcome Measures:
  • Phase 1 - Safety & Recommended Phase 2 Dose (RP2D) [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
    RP2D determined by MTD, post-DLT period toxicity, and pharmacokinetic data

  • Phase 2 - Progression-free survival rate [ Time Frame: No time limit ] [ Designated as safety issue: Yes ]
    6 month progression-free survival rate (PFS6) determined by tumor assessments, clinical tests and laboratory tests


Secondary Outcome Measures:
  • Secondary Outcome 1 Phase 2 - Response Rates [ Time Frame: No time limit ] [ Designated as safety issue: No ]
    Objective response rate, (ORR = CR + PR), PFS and OS determined by tumor assessments, clinical tests and laboratory tests

  • Secondary Outcome 2 Phase 2 - Safety and Tolerability [ Time Frame: No time limit ] [ Designated as safety issue: Yes ]
    Determined by clinical and laboratory tests, and AE assessments

  • Secondary Outcome 3 Phase 2 - PTEN expression [ Time Frame: No time limit ] [ Designated as safety issue: No ]
    PTEN expression associated with better PFS determined by laboratory tests

  • Secondary Outcome 4 Phase 2 - PI3K-pathway signaling [ Time Frame: No time limit ] [ Designated as safety issue: No ]
    Greater reduction in PI3K-pathway signaling associated with better PFS determined by laboratory tests and tumor assessments

  • Secondary Outcome 5 Phase 2 - PI3K and MAPK expression [ Time Frame: No time limit ] [ Designated as safety issue: No ]
    Responding tumors lack gene expression signatures of both PI3K and MAPK pathway activation, and progressing tumors demonstrate gene expression signatures of either PI3K or MAPK pathway activation - determined by laboratory tests and tumor assessments


Estimated Enrollment: 46
Study Start Date: June 2012
Estimated Study Completion Date: July 2015
Estimated Primary Completion Date: June 2014 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: BKM120 Combined with Vemurafenib (PLX4032)

    Phase I is 3+3 dose escalation study to identify the recommended phase 2 dose (RP2D)

    Dose Level -1: BKM120 60 mg daily, Vemurafenib 480 mg bid

    Dose Level 1: BKM120 60 mg daily, Vemurafenib 720 mg bid

    Dose Level 2: BKM120 80 mg daiy, Vemurafenib 720 mg bid

    Dose Level 3: BKM120 100 mg daiy, Vemurafenib 720 mg bid

    Dose Level 4: BKM120 100 mg daiy, Vemurafenib 960 mg bid

    Phase II is a single-stage, single arm prospective trial: patients will receive BKM120 and vemurafenib at the RP2D

Detailed Description:

The phase 1 portion of this trial is a dose escalation study; the phase 2 portion is a single-stage, single arm prospective clinical trial. All patients will receive continuous doses of vemurafenib twice a day and BKM120 once a day.

In the phase 1 portion of the study, there will be a 7 day lead-in period to allow for single dose pharmacokinetic analysis of BKM120 alone. Cycle 1 (28 days) is the dose-limiting toxicity (DLT) period. During phase 1, vemurafenib and BKM120 doses will be escalated using a standard 3+3 dose escalation scheme with the goal of identifying the recommended phase 2 dose.

In the phase 2 portion of the study, patients will receive continuous doses of vemurafenib and BKM120 starting on day 1 of the first cycle. In the phase 2 portion of the study, patients will receive vemurafenib and BKM120 at the recommended phase 2 dose.

  Eligibility

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

Inclusion Criteria

  1. Histologically or cytologically confirmed diagnosis of unresectable stage III and stage IV melanoma
  2. BRAFV600E or BRAFV600K mutation-positive
  3. Age ≥ 18 years
  4. ECOG performance status ≤ 2
  5. Patients must have at least one site of measurable disease (per RECIST for solid tumors)
  6. Life expectancy of ≥ 12 weeks
  7. Adequate bone marrow function as shown by: ANC ≥ 1.5 x 109/L, Platelets ≥ 100 x 109/L, Hb >9 g/dL
  8. Total calcium (corrected for serum albumin) within normal limits (biphosphonate use for malignant hypercalcemia control is not allowed)
  9. Magnesium ≥ the lower limit of normal
  10. Potassium within normal limits for the institution
  11. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) within normal range (or ≤ 3.0 x upper limit of normal (ULN) if liver metastases are present)
  12. Serum bilirubin within normal range (or ≤ 1.5 x ULN if liver metastases are present; or total bilirubin ≤ 3.0 x ULN with direct bilirubin within normal range in patients with well documented Gilbert Syndrome)
  13. Serum creatinine ≤ 1.5 x ULN or 24-hour clearance ≥ 50 mL/min
  14. Serum amylase ≤ ULN
  15. Serum lipase ≤ ULN
  16. INR ≤ 2
  17. Fasting plasma glucose ≤ 120 mg/dL (6.7 mmol/L)
  18. Negative serum pregnancy test within 48 hours before starting study treatment

Exclusion Criteria

  1. Patients who have received prior treatment with a PI3K inhibitor or a BRAF inhibitor, prior treatment with sorafenib is permitted.
  2. Patients with a known hypersensitivity to BKM120 or to its excipients
  3. Patients with untreated brain metastases are excluded; however, patients with metastatic CNS tumors may participate in this trial, if the patient is > 4 weeks from therapy completion (incl. radiation and/or surgery) and clinically stable at the time of study entry
  4. Patients with acute or chronic liver, renal disease or pancreatitis
  5. Patients with the following mood disorders as judged by the Investigator or a psychiatrist, or as a result of patient's mood assessment questionnaire:

    • Medically documented history of or active major depressive episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, history of suicidal attempt or ideation, or homicidal ideation
    • ≥ CTCAE grade 3 anxiety
    • Meets the cut-off score of ≥ 10 in the PHQ-9 or a cut-off of ≥ 15 in the GAD-7 mood scale, respectively, or selects a positive response of "1, 2, or 3" to question number 9 regarding potential for suicidal thoughts in the PHQ-9 (independent of the total score of the PHQ-9) will be excluded from the study unless overruled by the psychiatric assessment
  6. Patients with diarrhea ≥ CTCAE grade 2
  7. Patient has active cardiac disease including any of the following:

    • Left ventricular ejection fraction (LVEF) < 50% as determined by MUGA or ECHO
    • QTc > 480 msec on screening ECG (using the QTcF formula)
    • Personal or family history of prolonged QT syndrome
    • Angina pectoris that requires the use of anti-anginal medication
    • Ventricular arrhythmias except for benign premature ventricular contractions
    • Supraventricular and nodal arrythmias requiring a pacemaker or not controlled with medication
    • Conduction abnormality requiring a pacemaker
    • Symptomatic pericarditis
  8. Patient has a history of cardiac dysfunction including any of the following:

    • Myocardial infarction within the last 6 months, documented by persistent elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LVEF function
    • History of documented congestive heart failure (New York Heart Association functional classification III-IV)
    • Documented cardiomyopathy
  9. Poorly controlled diabetes mellitus (HbA1c > 8 %)
  10. Other concurrent severe and/or uncontrolled concomitant medical conditions that could cause unacceptable safety risks or compromise compliance with the protocol

    - Significant symptomatic deterioration of lung function; if clinically indicated, pulmonary function tests including measures of predicted lung volumes, DLco, O2 saturation at rest on room air should be considered to exclude pneumonitis or pulmonary infiltrates

  11. Impairment of GI function or GI disease that may significantly alter the absorption of BKM120 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
  12. Patients who have been treated with any hematopoietic colony-stimulating growth factors (e.g., G-CSF, GM-CSF) ≤ 2 weeks prior to starting study drug; erythropoietin or darbepoetin therapy, if initiated at least 2 weeks prior to enrollment, may be continued
  13. Patients who are currently receiving treatment with medication with a known risk to prolong the QT interval or inducing Torsades de Pointes and the treatment cannot either be discontinued or switched to a different medication prior to starting study drug
  14. Patients receiving chronic treatment with steroids or another immunosuppressive agent; topical applications, inhaled sprays, eye drops or local injections are allowed; patients with previously treated brain metastases, who are on stable low dose corticosteroids treatment for at least 14 days before start of study treatment are eligible
  15. Patients who have taken herbal medications and certain fruits within 7 days prior to starting study drug - herbal medications include, but are not limited to St. John's Wort, Kava, ephedra (ma huang), gingko biloba, DHEA, yohimbe, saw palmetto, and ginseng; fruits include CYP3A inhibitors: Seville oranges, grapefruit, pomelos, or exotic citrus fruits
  16. Patients who are currently treated with drugs known to be moderate and strong inhibitors or inducers of isoenzyme CYP3A, and the treatment cannot be discontinued or switched to a different medication prior to starting study drug; note that co-treatment with weak inhibitors of CYP3A is allowed).
  17. Patients who have received chemotherapy or targeted anticancer therapy ≤ 4 weeks (6 weeks for nitrosourea, antibodies or mitomycin-C) prior to starting study drug must have resolution of treatment related adverse events to baseline or grade 1 before starting the trial
  18. Patients who have received wide field radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy
  19. Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy
  20. Patients who are currently taking therapeutic doses of warfarin sodium or any other coumadin-derivative anticoagulant
  21. Women who are pregnant or breast feeding or adults of reproductive potential not employing an effective method of birth control; women of child-bearing potential must have a negative serum pregnancy test ≤ 72 hours prior to initiating treatment; double barrier contraceptives must be used through the trial by both sexes; oral, implantable, or injectable contraceptives are therefore not considered effective for this study

    • Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL [for US only: and estradiol < 20 pg/mL] or have had surgical bilateral oophorectomy (with or without hysterectomy) at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.
    • Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, must use highly effective contraception during treatment for 3 months in total after study drug discontinuation. Highly effective contraception is defined as either: True abstinence-when this is in line with the preferred and usual lifestyle of the subject, periodic abstinence and withdrawal are not acceptable methods of contraception; Sterilization-have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago; Male partner sterilization-for female subjects, the vasectomised male partner should be the sole partner for that patient; Use of a combination of any two of the following barrier methods of contraception-condom or Occlusive cap with spermicidal foam/gel/film/cream/vaginal suppository
    • Fertile males, defined as all males physiologically capable of conceiving offspring must use condom during treatment, for 3 months in total after study drug discontinuation and should not father a child in this period
  22. Known diagnosis of human immunodeficiency virus (HIV) infection
  23. History of another malignancy within 3 years, except cured or curable basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ of the cervix; patients with lesions curable by excision must have these lesions excised prior to the initiation of treatment on study
  24. Patient is unable or unwilling to abide by the study protocol or cooperate fully with the investigator
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01512251

Contacts
Contact: Alain Algazi, MD 415-353-7552 alain.algazi@ucsf.edu
Contact: Paula Fiermonte 415-885-7605 fiermontep@cc.ucsf.edu

Locations
United States, California
University of California, San Francisco Recruiting
San Francisco, California, United States, 94115
Contact: Alain Algazi, MD    415-353-7552    alain.algazi@ucsf.edu   
Sub-Investigator: Adil Daud, MD         
Sub-Investigator: Edward Cha, MD, PhD         
Sponsors and Collaborators
University of California, San Francisco
Novartis
  More Information

No publications provided

Responsible Party: Alain Algazi, Assistant Clinical Professor - Melanoma Oncology, University of California, San Francisco
ClinicalTrials.gov Identifier: NCT01512251     History of Changes
Other Study ID Numbers: Protocol 11952
Study First Received: December 20, 2011
Last Updated: May 20, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by University of California, San Francisco:
BKM120
BRAF
Melanoma
PI3K

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

ClinicalTrials.gov processed this record on November 25, 2014