Clinical Trials /

Study of RXDX-105, Potent RET Inhibitor in Patients With Advanced Lung Cancer and Other Solid Tumors

NCT01877811

Description:

This is a first-in-human, multicenter, open-label study consisting of 2 phases. Phase 1 is a dose escalation study of RXDX-105 (formerly known as CEP-32496) in patients with advanced solid tumors aimed at defining the recommended Phase 2 dose (RP2D) and schedule for administration. Phase 1b is a dose expansion in approximately 90 patients with advanced solid tumors with specific histologies and/or molecular alterations of interest. Patients in Phase 1b will be treated at the RP2D determined in Phase 1.

Related Conditions:
  • Colorectal Carcinoma
  • Malignant Solid Tumor
  • Melanoma
Recruiting Status:

Completed

Phase:

Phase 1

Trial Eligibility

Document

CEP-32496 in Patients With Advanced Solid Tumors in Phase 1 and Advanced <span class="go-doc-concept go-doc-disease">Melanoma</span> and Metastatic <span class="go-doc-concept go-doc-disease">Colorectal Cancer</span> in Phase 2

Title

  • Brief Title: CEP-32496 in Patients With Advanced Solid Tumors in Phase 1 and Advanced Melanoma and Metastatic Colorectal Cancer in Phase 2
  • Official Title: An Open-Label, Phase 1/Phase 2, Single-Agent Study of CEP-32496 in Patients With Advanced Solid Tumors in Phase 1 and in Patients With Advanced Melanoma and Metastatic Colorectal Cancer With BRAF Mutation in Phase 2
  • Clinical Trial IDs

    NCT ID: NCT01877811

    ORG ID: C32496/1105

    Trial Conditions

    Solid Tumors

    Melanoma

    Metastatic Colorectal Cancer

    Trial Interventions

    Drug Synonyms Arms
    CEP-32496 AC013773 CEP-32496

    Trial Purpose

    This is a first-in-human, multicenter, open-label study consisting of 2 phases. Phase 1 is a
    dose escalation study of CEP-32496 in patients with advanced solid tumors aimed at defining
    the RP2D and schedule for administration. In Phase 2 patients with advanced unresectable
    melanoma and metastatic colorectal cancer with BRAF V600E or BRAF V600K mutation will be
    treated at the recommended Phase 2 dose (RP2D) determined in Phase 1.

    Detailed Description

    The primary objective of Phase 1 is to determine the recommended Phase 2 dose (RP2D) of
    CEP-32496. The primary objective of Phase 2 is to evaluate the antitumor activity of
    CEP-32496 at the RP2D, as assessed by objective response rate (complete response [CR] or
    partial response [PR]) using Response Evaluation Criteria in Solid Tumors version 1.1
    (RECIST v1.1) in patients with advanced unresectable melanoma and metastatic colorectal
    cancer with BRAF mutation. Four groups of patients will be treated in Phase 2:

    - group A: patients with advanced unresectable melanoma with acquired resistance to BRAF
    inhibitors (ie, patients who have achieved a CR or PR as a best response to treatment
    with a prior BRAF inhibitor and subsequently became resistant) and patients who
    discontinued treatment with a BRAF inhibitor due to intolerance

    - group B: patients with advanced unresectable melanoma with primary resistance to BRAF
    inhibitors (ie, patients who maintained stable disease or had progressive disease as a
    best response to treatment with a prior BRAF inhibitor)

    - group C: patients with advanced unresectable melanoma who are nave to treatment with
    BRAF inhibitors

    - group D: patients with metastatic colorectal cancer who are nave to treatment with
    BRAF inhibitors

    Each phase of this study will consist of a 28-day screening period. Patients will be treated
    in 28-day treatment cycles until disease progression, unacceptable toxicity, withdrawal of
    consent, or protocol specified parameters to stop treatment. Patients in Phase 1 will be
    followed for a minimum of 6 months after the last dose of study treatment, and patients in
    Phase 2 will be followed to collect further anticancer information for up to 12 months after
    the end-of-treatment visit for the last discontinued patient on the study.

    Trial Arms

    Name Type Description Interventions
    CEP-32496 Experimental CEP-32496

    Eligibility Criteria

    Inclusion Criteria:

    1. Phase 1 only: Patients must have histological or cytological evidence of a solid
    tumor which is refractory to available therapy or for which no effective standard
    therapy exists. The patient may have received monotherapy with 1 or more BRAF
    inhibitors.

    2. Phase 2 only: Patients must have histologically or cytologically confirmed advanced
    unresectable cutaneous melanoma (Stage IIIC and IV per American Joint Committee on
    Cancer [AJCC]) and BRAF V600E or BRAF V600K mutation or relapsed/refractory
    metastatic colorectal cancer and BRAF V600E or BRAF V600K mutation.

    - Previously existing BRAF V600E or BRAF V600K mutation results using a test
    approved by the FDA or from an accredited laboratory (CLIA certified or
    equivalent) will be accepted.

    - If documented results are not available, then archived or fresh tumor tissue
    samples suitable for biomarker analysis must be available for testing by an
    accredited laboratory (CLIA certified or equivalent).

    3. Patients may have received any number of prior systemic treatments for their cancer.
    However, for patients in Phase 2, groups A and B, prior treatment with only 1 BRAF
    inhibitor or MEK inhibitor monotherapy is permitted. Phase 2 patients with metastatic
    colorectal cancer (group D) must have received 1 or more fluoropyrimidine,
    oxaliplatin, or irinotecan based chemotherapy.

    4. The patient has measurable disease and documented progression on or after last prior
    treatment according to Response Evaluation Criteria in Solid Tumors (RECIST) version
    1.1

    5. The patient must have an Eastern Cooperative Oncology Group (ECOG) performance status
    of 0 or 1 for Phase 1 or 0, 1, or 2 for Phase 2.

    6. Other inclusion criteria apply.

    Exclusion Criteria:

    1. For patients in Phase 1 only, the patient has primary brain tumor or ocular melanoma.

    2. For patients in Phase 2 groups C or D only, the patient received previous treatment
    with a selective BRAF inhibitor or MEK inhibitor (prior treatment with sorafenib
    allowed).

    3. The patient was treated with systemic anticancer therapy or investigational agent
    within 3 weeks prior to start of study drug treatment (6 weeks for bevacizumab and
    immunotherapy).

    4. The patient had major surgery within 21 days or less prior to starting of the study
    drug or who have not recovered from adverse effects of such therapy.

    5. The patient had radiotherapy within 2 weeks prior to start of study drug treatment.

    Patients must have recovered from all radiotherapy-related toxicities.

    6. The patient has known central nervous system (CNS) metastases. Patients with any
    clinical signs of CNS metastases must have a CT or MRI of the brain to rule out CNS
    metastases in order to be eligible for participation in the study. Patients who have
    had brain metastases treated with radiotherapy or surgically removed with no residual
    disease confirmed by imaging should be clinically stable and off corticosteroid
    treatment at least 3 weeks prior to start of study drug treatment.

    7. The patient has a QTc interval greater than 470 msec.

    8. The patient has a major active infection requiring parenteral antibiotics.

    9. The patient has a severe or unstable medical condition such as congestive heart
    failure (New York Heart Association [NYHA] Class III or IV), ischemic heart disease,
    uncontrolled hypertension, uncontrolled diabetes mellitus, psychiatric condition, as
    well as an ongoing cardiac arrhythmia requiring medication (grade 2, according to
    NCI Common Terminology Criteria for Adverse Events [CTCAE] v4.03), myocardial
    infarction within 6 months prior to starting study treatment, or any other
    significant or unstable concurrent medical illness that in the opinion of the
    investigator would preclude protocol therapy.

    10. Other exclusion criteria apply.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Objective Response Rate

    Secondary Outcome Measures

    Duration of Objective Response

    Disease Control Rate

    Progression-free Survival

    Overall Survival

    Maximum observed plasma drug concentration (Cmax)

    Time of maximum observed plasma drug concentration (tmax)

    Area under the plasma drug concentration versus time curve from time 0 to infinity (AUC0-)

    Area under the plasma drug concentration versus time curve from time 0 to the last measureable drug concentration (AUC0-t)

    Area under the plasma drug concentration versus time curve from time 0 to 24 hours

    Terminal elimination rate constant (z)

    Terminal elimination half-life (t1/2)

    Apparent clearance of study drug from plasma (CL/F)

    Apparent volume of distribution (V/F)

    Percentage extrapolation

    Predicted accumulation ratio

    AUC for 1 dosing interval following multiple doses only (AUC)

    AUC0-t

    Cmax

    Tmax

    Observed accumulation ratio (Robs)

    Steady-state accumulation ratio (Rss)

    Dose Limiting Toxicities

    Occurrence of Adverse Events

    Trial Keywords

    BRAF inhibitor

    solid tumors

    melanoma

    colorectal cancer