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Phase 1/2 Study of PI-3K Inhibition With PX-866 Combined With Vemurafenib (BRAF Inhibitor) in Patients With BRAF-mutant Cancer Including Advanced Melanoma

Phase 1/Phase 2
18 Years
Open (Enrolling)
Advanced BRAF-mutant Cancers

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Trial Information

Phase 1/2 Study of PI-3K Inhibition With PX-866 Combined With Vemurafenib (BRAF Inhibitor) in Patients With BRAF-mutant Cancer Including Advanced Melanoma

This is a Phase 1 / 2 open-label study of PX-866 given in combination with vemurafenib to
patients with BRAF-mutant cancer, including advanced melanoma.

Phase 1 will use a 3+3 dose escalation design to evaluate up to three dose levels of PX-866
in combination with up to two dose levels of vemurafenib in order to identify the maximal
tolerated dose/recommended dose (MTD/RD) of both PX-866 and vemurafenib to be used in Phase
2. Vemurafenib will be administered orally twice per day on days 1-28 of all cycles except
cycle 1, where vemurafenib will be administered on days 9-28 to allow for PK assessments).
PX-866 will be administered once per day on days 1-28 of each cycle.

Phase 2 will evaluate the antitumor activity and safety of PX-866 given to patients
randomized 2:1 to receive combination with vemurafenib at the doses recommended from Phase 1
compared with vemurafenib alone administered at the approved dose orally BID. All
treatments will be administered on a 28-day cycle.

Patients randomized to receive single-agent vemurafenib may cross-over to receive the
combination treatment at the time of progression. Patients will be evaluated for progression
approximately every 8 weeks for the initial 24 weeks and every 12 weeks thereafter. All
patients with stable disease (SD) or better, will receive repeat cycles until disease
progression (PD), unacceptable toxicity, or withdrawal of consent.

Inclusion Criteria:

- ≥ 18 years at time of consent

- If a sexually active male or a sexually active female of child-bearing potential,
agrees to use a highly effective form of contraception (including birth control
pills, barrier device, or intrauterine device)from the time of consent 90 days
following the last dose of study drug

- If female of child-bearing potential, negative pregnancy test

- For Phase 1: must have histologically or cytologically-confirmed advanced cancer that
is BRAF mutation-positive (V600E or V600K) for which there is no remaining standard
therapy with curative potential. Patients must have disease sites amenable to biopsy.
For Phase 2: must have histologically or cytologically-confirmed BRAF
mutation-positive (V600E or V600K) advanced (defined as unresectable Stage IIIC or
IV) melanoma that has not been treated with a selective BRAF inhibitor

- For Phase 1: must have measurable or non-measurable disease. For Phase 2: must have
measurable disease per RECIST 1.1

- For Phase 1: no restriction on number of prior therapy regimens. For Phase 2: the
following restrictions on prior therapy apply: 1) must not have been treated with a
selective BRAF inhibitor and must not have had more than 2 prior treatment regimens
for advanced metastatic disease; 2) must have completed prior cytotoxic chemotherapy
a minimum of 4 weeks prior to starting PX-866 and/or vemurafenib (except for BCNU
and/or mitomycin C, which must have been completed a minimum of 6 weeks prior to
starting therapy). Prior biologic therapy and localized radiation therapy must have
been completed a minimum of 2 weeks prior to starting therapy.

- All toxicities related to prior cancer therapies other than alopecia must have
resolved to Grade 1 or less

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

- In the opinion of the clinical investigator, life expectancy > 3 months

- Adequate hematologic function

- Adequate hepatic function

- Serum creatinine < 2.0 mg/dL

- Adequate cardiac function

- Corrected QTc must be <480 milliseconds

Exclusion Criteria:

- May not be receiving any other investigational agents

- Active central nervous system (CNS) metastases are excluded. Patients with a history
of CNS metastasis, who have been treated prior to enrollment, must be stable for
eight weeks after completion of treatment. These patients must have undergone
appropriate imaging studies and currently be on a stable, lowest possible dose of

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to PX-866 or vemurafenib

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

- Uncorrectable electrolyte abnormalities or long QT syndrome

- Poorly controlled diabetes mellitus

- Pregnant, breastfeeding, or planning to become pregnant

- Known to be human immunodeficiency virus (HIV)-positive

- Inability to swallow pills

- Previous treatment with a phosphatidylinositol-3-kinase (PI-3K) inhibitor

- Any other significant medical or psychiatric condition that in the opinion of the
investigator renders the patient inadequate for participation

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Incidence and severity of adverse events (phase 1)

Outcome Time Frame:

28 days

Safety Issue:



United States: Food and Drug Administration

Study ID:




Start Date:

August 2012

Completion Date:

March 2015

Related Keywords:

  • Advanced BRAF-mutant Cancers
  • PX-866
  • BRAF-mutant cancers
  • Advanced melanoma
  • BRAF inhibitor
  • Vemurafenib
  • Zelboraf
  • PI-3K inhibitor
  • Melanoma



University of Pittsburgh Cancer InstitutePittsburgh, Pennsylvania  15213
Vanderbilt-Ingram Cancer CenterNashville, Tennessee  37232-6838
University of PennsylvaniaPhiladelphia, Pennsylvania  19104
H. Lee Moffitt Cancer CenterTampa, Florida  33612
New York UniversityNew York, New York  10016