Clinical Trials /

Navitoclax and Sorafenib Tosylate in Treating Patients With Relapsed or Refractory Solid Tumors

NCT02143401

Description:

This phase I trial studies the side effects and the best dose of navitoclax when given together with sorafenib tosylate in treating patients with solid tumors that have returned (relapsed) or do not respond to treatment (refractory). Navitoclax and sorafenib tosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Navitoclax and Sorafenib Tosylate in Treating Patients With Relapsed or Refractory Solid Tumors
  • Official Title: A Phase I Trial of ABT-263 (Navitoclax), a Bcl-2 Inhibitor, and Sorafenib (Nexavar) in Patients With Relapsed or Refractory Solid Organ Tumors

Clinical Trial IDs

  • ORG STUDY ID: NCI-2014-01043
  • SECONDARY ID: NCI-2014-01043
  • SECONDARY ID: MC1315
  • SECONDARY ID: 9608
  • SECONDARY ID: 9608
  • SECONDARY ID: UM1CA186686
  • NCT ID: NCT02143401

Conditions

  • Cirrhosis
  • Hepatitis B Infection
  • Hepatitis C Infection
  • Metastatic Malignant Solid Neoplasm
  • Recurrent Hepatocellular Carcinoma
  • Recurrent Malignant Solid Neoplasm
  • Refractory Malignant Neoplasm
  • Stage IV Hepatocellular Carcinoma AJCC v7
  • Unresectable Solid Neoplasm

Interventions

DrugSynonymsArms
NavitoclaxA-855071.0, ABT-263, BcI-2 Family Protein Inhibitor ABT-263Treatment (navitoclax, sorafenib tosylate)
Sorafenib TosylateBAY 43-9006 Tosylate, BAY 54-9085, Nexavar, sorafenibTreatment (navitoclax, sorafenib tosylate)

Purpose

This phase I trial studies the side effects and the best dose of navitoclax when given together with sorafenib tosylate in treating patients with solid tumors that have returned (relapsed) or do not respond to treatment (refractory). Navitoclax and sorafenib tosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the maximum tolerated dose (MTD) of the combination of navitoclax and
      sorafenib tosylate (sorafenib) in patients with advanced solid tumors. (Dose escalation
      cohort) II. To better characterize the toxicity profile of the combination of navitoclax and
      sorafenib. (Dose expansion cohort)

      SECONDARY OBJECTIVES:

      I. To identify any activity of this treatment combination in patients with metastatic cancer.
      (Dose escalation cohort) II. To seek preliminary evidence of activity of this treatment
      combination in patients with hepatoma. (Dose expansion cohort)

      CORRELATIVE OBJECTIVES:

      I. To determine whether the combination of navitoclax and sorafenib induces apoptosis that
      can be detected by peripheral blood biomarker analysis. (Dose escalation cohort) II. To
      assess peripheral blood biomarkers and pharmacokinetics in a more homogenous population.
      (Dose expansion cohort) III. To determine whether treatment is associated with Mcl-1 down
      regulation in hepatocellular carcinoma (HCC) at the maximum tolerated dose (MTD). (Dose
      expansion cohort) IV. To assess in a preliminary fashion whether pretreatment tumor cell
      levels of Mcl-1 predict response to this regimen through serial biopsies. (Dose expansion
      cohort)

      OUTLINE: This is a dose-escalation study of navitoclax.

      Patients receive navitoclax orally (PO) once daily (QD) on days 1-21 (days 1-28 cycle of 1
      only) and sorafenib tosylate PO twice daily (BID) on days 1-21. Cycles repeat every 21 days
      in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 3 months.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (navitoclax, sorafenib tosylate)ExperimentalPatients receive navitoclax PO QD on days 1-21 (days 1-28 cycle of 1 only) and sorafenib tosylate PO BID on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • Navitoclax
  • Sorafenib Tosylate

Eligibility Criteria

        Inclusion Criteria:

          -  For Dose Escalation Cohort: Patients must have histologically confirmed malignancy
             that is metastatic or unresectable and for which standard curative or palliative
             measures do not exist or are no longer effective

          -  For Dose Expansion Cohort: HCC patients only: HCC confirmed by biopsy OR diagnosed by
             clinical and radiologic criteria; all of the following criteria must be met or a
             biopsy is required:

               -  Known cirrhosis or chronic hepatitis B virus (HBV) or hepatitis C virus (HCV)
                  infection

               -  Hypervascular liver masses > 2 cm, and either serum alpha-fetoprotein (AFP) > 400
                  ng/ml

               -  AFP > three times normal and doubling in value in the antecedent 3 months

               -  In the expansion cohort, prior treatment with sorafenib as first-line therapy
                  allowed

          -  Any number of the following prior therapies is allowed:

               -  Chemotherapy >= 28 days prior to registration

               -  Mitomycin C/nitrosoureas >= 42 days prior to registration

               -  Immunotherapy >= 28 days prior to registration

               -  Biologic therapy >= 28 days prior to registration

               -  Targeted therapy >= 28 days prior to registration

               -  Radiation therapy >= 28 days prior to registration

               -  Radiation to < 25% of bone marrow

          -  HCC patients only: prior regional treatments for liver metastasis are permitted
             including:

               -  Selective internal radiation therapy such as brachytherapy, cyber knife,
                  radiolabeled microsphere embolization, etc.

               -  Hepatic artery chemoembolization

               -  Hepatic artery embolization

               -  Hepatic artery infusional chemotherapy

               -  Radiofrequency ablation

               -  NOTE: patients must be >= 4 weeks from treatment and show progressive
                  measurable/evaluable disease in the liver after regional therapy or must have
                  measurable disease outside the liver

          -  HCC patients only: Child Pugh class A or B7 liver disease

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2

          -  Life expectancy of > 3 months

          -  Leukocytes >= 3,000/mcL

          -  Absolute neutrophil count >= 1,500/mcL (patients may be treated with hematopoietic
             growth factors to achieve or maintain this level)

          -  Hemoglobin >= 9.0 g/dL

          -  International normalized ratio (INR) =< 1.4

          -  Platelets >= 100,000/mm^3

          -  Total bilirubin =< 1.5 x ULN (institutional upper limit of normal) (patients with
             Gilbert's syndrome may have direct bilirubin > 2.5 x ULN)

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 2.5 x institutional ULN

          -  Serum creatinine =< 1.5 x ULN

          -  Able to swallow and retain oral medication

          -  Negative serum pregnancy test =< 7 days prior to registration for women of
             childbearing potential

               -  NOTE: women will be considered not of childbearing potential if they are
                  surgically sterile (bilateral oophorectomy or hysterectomy) and/or
                  post-menopausal (amenorrheic for at least 12 months)

          -  Ability to understand and the willingness to sign a written informed consent document

          -  Willing to provide tissue samples for correlative research purposes

        Exclusion Criteria:

          -  Unresolved toxicity of National Cancer Institute Common Terminology Criteria for
             Adverse Events, version 4.0 (NCI CTCAE v 4.0) grade 2 or higher from previous
             anti-cancer therapy, except alopecia

          -  Receiving any other investigational agents =< 28 days prior to registration

          -  Known brain metastases (even if treated)

          -  Known portal hypertension or history of variceal bleeding; these patients are felt to
             be at increased risk of bleeding if they experience navitoclax-induced
             thrombocytopenia

          -  Inadequately controlled hypertension (systolic blood pressure of > 150 mmHg or
             diastolic pressure > 90 mmHg on anti-hypertensive medications)

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to navitoclax or sorafenib

          -  Current use of anticoagulation; NOTE: use of low-dose anticoagulation medications that
             are used to maintain the patency of a central intravenous catheter is allowed

          -  Corrected QT (QTc) interval > 480 msec on baseline electrocardiogram (EKG)

          -  Documented history of prolonged QTc interval =< 6 months prior to registration

          -  Receiving any medications that prolong the QTc and have a known risk for Torsades de
             pointes; providers should use caution with drugs with possible increased risk for
             Torsades de pointes; NOTE: patient will be eligible if they can be taken off these
             medications prior to initiation of therapy and no less than 4 half-lives of the
             medication

          -  Current use of certain concomitant medications due to mechanistic-based platelet
             toxicities from navitoclax: clopidogrel, ibuprofen, tirofiban and other
             anticoagulants, drugs or herbal supplements that effect platelet function; NOTE:
             antiplatelet use is prohibited during the use of navitoclax; subjects who have
             previously received aspirin therapy for thrombosis prevention may resume a low dose
             (i.e., maximum 100 mg QD) of aspirin if platelet counts are stable (>= 50,000/mm^3)
             through 6 weeks of navitoclax administration; all decisions regarding treatment with
             aspirin therapy will be determined by the principal investigator in conjunction with
             the medical monitor

          -  Current use of strong CYP3A inhibitors such as ketoconazole, itraconazole,
             voriconazole, posaconazole, nefazodone, and clarithromycin are prohibited; NOTE:
             moderate inhibitors of CYP3A4 should be used with caution; navitoclax is a moderate
             inhibitor of CYP2C8 and a strong inhibitor of CYP2C9; caution should be exercised when
             dosing navitoclax concurrently with CYP2C8 and CYP2C9 substrates; common CYP2C8
             substrates include paclitaxel, statins and repaglinide; CYP2C9 substrates include
             celecoxib, phenytoin and warfarin; when possible, investigators should switch to
             alternative medications or monitor the patients closely

          -  Concurrent use of strong CYP3A4/5 inducers such as carbamazepine, phenytoin, rifampin,
             and St. John's wort are prohibited

          -  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

          -  Any of the following:

               -  Pregnant women

               -  Nursing women

               -  Women of childbearing potential who are unwilling to employ adequate
                  contraception; NOTE: should a woman become pregnant or suspect she is pregnant
                  while she or her partner is participating in this study, she should inform her
                  treating physician immediately; the effects of navitoclax on the developing human
                  fetus are unknown; for this reason and because other therapeutic agents used in
                  this trial are known to be teratogenic, women of child-bearing potential and men
                  must agree to use adequate contraception using one of the methods listed below
                  prior to study entry, for the duration of study participation, and up to 90 days
                  following completion of therapy:

                    -  Total abstinence from sexual intercourse (minimum one complete menstrual
                       cycle prior to study drug administration)

                    -  Vasectomized male subject or vasectomized partner of female subjects

                    -  Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) for
                       at least 3 months prior to study drug administration; if the subject is
                       currently using a hormonal contraceptive, she should also use a barrier
                       method during this study and for 1 month after study completion

                    -  Intrauterine device (IUD)

                    -  Double-barrier method: male condom plus diaphragm or vaginal cap with
                       spermicide (contraceptive sponge, jellies or creams)

                    -  Additionally, male subjects (including those who are vasectomized) whose
                       partners are pregnant or might be pregnant must agree to use condoms for the
                       duration of the study and for 90 days following completion of therapy

          -  Human immunodeficiency virus (HIV)-positive patients on highly active antiretroviral
             therapy (HAART) are excluded due to possible drug-drug interactions with the
             investigational agent(s)

          -  Underlying condition predisposing them to bleeding or currently exhibits signs of
             clinically significant bleeding

          -  Recent history of non-chemotherapy-induced thrombocytopenic-associated bleeding =< 1
             year prior to the registration

          -  History of cardiovascular disease (e.g., myocardial infraction [MI], thrombotic or
             thromboembolic event in the last 6 months)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD) of navitoclax
Time Frame:28 days
Safety Issue:
Description:Will be defined as the dose level below the lowest dose that induces dose-limiting toxicity in at least one-third of patients (at least 2 of a maximum of 6 new patients) per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v.) 4.0.

Secondary Outcome Measures

Measure:Tumor response
Time Frame:Up to 3 months
Safety Issue:
Description:Will be assessed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline version 1.1. Response will be summarized by simple descriptive summary statistics delineating complete and partial responses as well as stable and progressive disease. The waterfall plot may be used to display best tumor response. Exploratory analysis of the relationship between response and other clinical endpoints may be performed.
Measure:Time until any treatment related toxicity
Time Frame:Up to 3 months
Safety Issue:
Description:The data on time-related variables will be summarized descriptively.
Measure:Time until treatment related grade 3+ toxicity
Time Frame:Up to 3 months
Safety Issue:
Description:The data on time-related variables will be summarized descriptively.
Measure:Time until hematologic nadirs (white blood cell, absolute neutrophil count, platelets)
Time Frame:Up to 3 months
Safety Issue:
Description:The data on time-related variables will be summarized descriptively.
Measure:Time to progression
Time Frame:Up to 3 months
Safety Issue:
Description:The data on time-related variables will be summarized descriptively.
Measure:Time to treatment failure
Time Frame:From registration to documentation of progression, unacceptable toxicity, or refusal to continue participation by the patient, assessed up to 3 months
Safety Issue:
Description:The data on time-related variables will be summarized descriptively.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

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