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A Phase 1 Study Evaluating CB-5083 in Subjects With Advanced Solid Tumors

NCT02243917

Description:

This is a multicenter, open-label, Phase 1 study of orally administered CB-5083 in adult subjects with advanced metastatic solid tumors. The study will be conducted in 2 parts: an initial Dose Escalation Phase (Phase 1a) of CB-5083 in subjects with advanced metastatic solid tumors who have progressed or are non-responsive to available therapies and for which no standard therapy exists, followed by a Dose Expansion Phase (Phase 1b) which will include 1 to 4 arms: one arm in subjects with RAS mutated mCRC; optionally, at sponsors discretion, 3 additional arms may be added for subjects with advanced RCC, advanced pNET, or solid tumors with mutations in the RAS-MAPK pathway.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Terminated

Phase:

Phase 1

Trial Eligibility

Document

A Phase 1 Study Evaluating <span class="go-doc-concept go-doc-intervention">CB-5083</span> in Patients With Advanced Solid Tumors

Title

  • Brief Title: A Phase 1 Study Evaluating CB-5083 in Patients With Advanced Solid Tumors
  • Official Title: A Phase 1, Open-Label, Dose Escalation and Dose Expansion Study Evaluating the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Effects of Orally Administered CB-5083 in Patients With Advanced Solid Tumors
  • Clinical Trial IDs

    NCT ID: NCT02243917

    ORG ID: CLC-101

    Trial Conditions

    Advanced Solid Tumors

    Trial Interventions

    Drug Synonyms Arms
    CB-5083 Dose Escalation Stage - CB-5083, Dose Expansion Stage - CB-5083

    Trial Purpose

    This is a multicenter, open-label, phase 1 study of orally administered CB-5083 in adult
    patients with advanced solid tumors who have progressed or are non-responsive to available
    therapies and for which no standard therapy exists. The study will be conducted in 2 parts:
    an initial Dose Escalation Phase (phase 1a) of CB-5083 in patients with advanced solid
    tumors, followed by a dose expansion phase (phase 1b) which will include 2 parallel arms:
    one in patients with advanced pNETs and the second one in patients with advanced solid
    tumors carrying K RAS mutations.

    Detailed Description

    The objectives of the Dose Escalation Phase are to determine the safety, tolerability, PK
    and pharmacodynamic profiles as well as the MTD and RP2D of orally administered CB-5083. The
    objectives of the dose expansion phase are to confirm the safety and tolerability of the
    RP2D, to further assess the PK and pharmacodynamic profiles and to evaluate the preliminary
    anti-tumor activity of CB-5083 in patients with tumors for which there is biologic
    plausibility of unique sensitivity to CB-5083 mechanism of action (MOA) based on
    pre-clinical data.

    Trial Arms

    Name Type Description Interventions
    Dose Escalation Stage - CB-5083 Experimental CB-5083 CB-5083
    Dose Expansion Stage - CB-5083 Experimental CB-5083 CB-5083

    Eligibility Criteria

    Inclusion Criteria:

    For both Escalation and Expansion arms:

    1. Males and females 18 years of age;

    2. Eastern Cooperative Oncology Group (ECOG) Performance Status of 1

    3. Acceptable bone marrow and organ function at screening

    4. Left ventricular ejection fraction informed (LVEF) 55%;

    5. Ability to swallow and retain oral medications;

    6. Negative serum beta-human Chorionic Gonadotropin (-hCG) test in women of
    childbearing potential (WOCBP); and

    7. Willing and able to provide written informed consent and comply with the requirements
    of the study.

    8. Dose Escalation arm, only - Histologically confirmed advanced solid tumor for which
    standard therapy does not exist or is no longer effective

    9. Dose Expansion arm, pNET Cohort only - Histologically confirmed low-grade or
    intermediate-grade, unresectable or metastatic pNET tumor with radiological
    documentation of disease progression < 12 months prior to enrollment for which
    standard therapy does not exist or is no longer effective. Functional and
    non-functional tumors can be included;

    10. Dose Expansion arm, K-RAS Cohort only - Histologically confirmed malignancy with a
    K-RAS mutation that is metastatic or unresectable and for which standard therapy does
    not exist or is no longer effective.

    Exclusion Criteria:

    Both arms

    1. Any prior treatment (with the exception of somatostatin analogues, which are allowed
    before and during the study in pNET patients at the investigator discretion in pNET
    patients) such as chemotherapy, immunomodulatory drug therapy, anti-neoplastic
    hormonal therapy (unless dose has been stable for 3 months prior to Baseline and will
    remain stable during the study), immunosuppressive therapy, or corticosteroids
    (unless administered to prevent contrast material reactions during radiographic
    procedures) received within the past 28 days or 5 half-lives, whichever is shorter.

    2. Presence of an acute or chronic toxicity resulting from prior chemotherapy, with the
    exception of alopecia, that has not resolved to grade 1;

    3. Received radiotherapy within the last 21 days (limited palliative radiation is
    allowed if 14 days prior);

    4. Patient with primary brain tumors or known central nervous system (CNS) metastases;

    5. Major surgery < 28 days from the start of treatment (major surgery is defined as a
    procedure requiring general anesthesia);

    6. Minor surgery <14 days from the start of treatment (insertion of a vascular access
    device is not considered major or minor surgery);

    7. Active infection requiring systemic therapy;

    8. Known to be human immunodeficiency virus (HIV) positive or have an acquired
    immunodeficiency syndrome-related illness;

    9. Uncontrolled congestive heart failure, angina, myocardial infarction, cerebrovascular
    accident, coronary/peripheral artery bypass graft surgery, transient ischemic attack,
    or pulmonary embolism within 3 months prior to initiation of study drug;

    10. History of or ongoing cardiac dysrhythmias requiring treatment, atrial fibrillation
    of any grade, or persistent prolongation of the QTc;

    11. History of esophageal bleeding due to varices;

    12. Gastrointestinal disease that may interfere with the absorption of
    orally-administered drugs;

    13. History of inflammatory bowel disease or other illness resulting in chronic diarrhea;

    14. Known achlorhydria or history of gastrointestinal surgery that could reduce the
    acidity of the stomach;

    15. Acute pancreatitis or cholecystitis within 6 months prior to Baseline;

    16. Cirrhosis with severe liver dysfunction;

    17. Previous malignancy, except for basal-cell or squamous cell carcinoma of the skin or
    carcinoma-in-situ of the uterine cervix. Patients with other malignancies are
    eligible if they have remained disease free for at least 2 years prior to study
    entry;

    18. Any severe, acute, or chronic medical or psychiatric condition, or laboratory
    abnormality that may increase the risk associated with study participation or study
    drug administration, may interfere with the informed consent process and/or with
    compliance with the requirements of the study, or may interfere with the
    interpretation of the study results and, in the Investigator's opinion, would make
    the patient inappropriate for entry into this study;

    19. Use of any investigational agents within 28 days or 5 half-lives (whichever is
    shorter) prior to Baseline;

    20. Concomitant treatment with pharmaceutical or herbal agents, which are potent
    inhibitors or inducers of cytochrome P450 (CYP) enzymes 2C9, 2C19, and 3A4 or are
    primarily metabolized by CYP 2C8 and 2C9. In addition, concomitant treatment with
    agents known to be substrates of the breast cancer resistance protein (BCRP) efflux
    pump is also excluded;

    21. Concomitant use of drugs with a risk of causing prolonged QTc and/or Torsades de
    Pointes or a history of risk factors for Torsades de Pointes;

    22. Concomitant use of any medication that alters stomach pH;

    23. Pregnant or lactating female; and

    24. Women of childbearing potential, or men who partner with a woman of childbearing
    potential, unless they agree to use dual barrier contraceptive methods which, in the
    Investigator's opinion, are effective and adequate for that patient's circumstances
    while on study drug and for 3 months afterward.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Dose Escalation Stage - the dose limiting toxicities (DLTs), using NCI CTCAE v4.0, of oral CB-5083 in patients with advanced tumors

    Dose Escalation Stage - the pharmacokinetic profile (PK) of oral CB-5083 in patients with advanced solid tumors; parameters include AUC, Cmax, Tmax and T1/2

    Dose Expansion Stage - safety of CB-5083 at dose determined at end of Dose Esc. Stage, in patients with advanced pancreatic neuroendocrine tumors (pNET) and Kirsten rat sarcoma (K-RAS) mutated solid tumors; parameters include ECOG performance status

    Secondary Outcome Measures

    Dose Escalation Stage - the pharmacodynamic (PD)effects of CB-5083 through the measurement of polyubiquitin accumulation (PUA) in peripheral blood mononuclear cells (PBMCs)

    Dose Expansion Stage - PK and PD profiles of CB-5083; PK parameters to include AUC, Cmax, Tmax and T1/2; PD effects through the measurement of PUA in PBMCs

    Dose Expansion Stage - anti tumor activity in certain patients, using the Response Evaluation Criteria in Solid Tumors (RECIST), v1.1

    Trial Keywords