Clinical Trials /

Navitoclax and Vistusertib in Treating Patients With Relapsed Small Cell Lung Cancer and Other Solid Tumors

NCT03366103

Description:

This phase I/II trial studies the best dose and side effects of navitoclax and how well it works when given together with vistusertib in treating patients with small cell lung cancer and solid tumors that have come back (relapsed). Drugs used in chemotherapy, such as navitoclax, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Vistusertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving navitoclax and vistusertib may work better than navitoclax alone in treating patients with small cell lung cancer and solid tumors.

Related Conditions:
  • Malignant Solid Tumor
  • Small Cell Lung Carcinoma
Recruiting Status:

Suspended

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Navitoclax and Vistusertib in Treating Patients With Relapsed Small Cell Lung Cancer and Other Solid Tumors
  • Official Title: Phase 1/2 Study of Navitoclax Plus Vistusertib in Patients With Relapsed Small Cell Lung Cancer (SCLC) and Other Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: NCI-2017-00037
  • SECONDARY ID: NCI-2017-00037
  • SECONDARY ID: ETCTN10070
  • SECONDARY ID: 10070
  • SECONDARY ID: 10070
  • SECONDARY ID: UM1CA186691
  • NCT ID: NCT03366103

Conditions

  • Metastatic Malignant Solid Neoplasm
  • Recurrent Lung Small Cell Carcinoma
  • Recurrent Malignant Solid Neoplasm
  • Stage III Lung Small Cell Carcinoma AJCC v7
  • Stage IIIA Lung Small Cell Carcinoma AJCC v7
  • Stage IIIB Lung Small Cell Carcinoma AJCC v7
  • Stage IV Lung Small Cell Carcinoma AJCC v7
  • Unresectable Solid Neoplasm

Interventions

DrugSynonymsArms
NavitoclaxA-855071.0, ABT-263, BcI-2 Family Protein Inhibitor ABT-263Treatment (navitoclax, vistusertib)
VistusertibAZD 2014, AZD-2014, AZD2014Treatment (navitoclax, vistusertib)

Purpose

This phase I/II trial studies the best dose and side effects of navitoclax and how well it works when given together with vistusertib in treating patients with small cell lung cancer and solid tumors that have come back (relapsed). Drugs used in chemotherapy, such as navitoclax, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Vistusertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving navitoclax and vistusertib may work better than navitoclax alone in treating patients with small cell lung cancer and solid tumors.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To evaluate the safety and tolerability of the combination of navitoclax and vistusertib
      in patients with advanced solid tumors. (Phase I) II. To determine the maximum tolerated dose
      (MTD), dose limiting toxicities (DLT), and recommended phase 2 doses (RP2D) of navitoclax and
      vistusertib. (Phase I) III. To determine the objective response rate (ORR), defined as
      complete plus partial response, of the combination of navitoclax and vistusertib in patients
      with recurrent small cell lung cancer (SCLC). (Phase II)

      SECONDARY OBJECTIVES:

      I. To evaluate the pharmacokinetics of navitoclax and vistusertib when administered together.
      (Phase I) II. To observe and record anti-tumor activity. (Phase I) III. To confirm the safety
      and tolerability of navitoclax and vistusertib at the RP2D. (Phase II) IV. To estimate
      progression free survival (PFS) and overall survival (OS) of the combination of navitoclax
      and vistusertib at the RP2D. (Phase II) V. To estimate disease control rate (DCR) of the
      combination of navitoclax and vistusertib at the RP2D. (Phase II)

      CORRELATIVE OBJECTIVES:

      I. To assess pharmacodynamic changes in levels of phosphorylated 4EBP1 (p4EBP1) the ratio of
      p4EBP1 to total (p4EBP1/4EBP1) in paired pre-treatment and on-treatment biopsies at the RP2D.
      (Phase II) II. To correlate changes in BAX and MCL-1 with response. (Phase II) III. To
      estimate the baseline inter-patient variability in p4EBP1, pS6, BAX, and MCL-1. (Phase II)
      IV. To explore exposure-response relationships between navitoclax and vistusertib exposure
      and the pharmacodynamic endpoints (safety, efficacy, and laboratory correlatives). (Phase II)

      OUTLINE: This is a phase I, dose-escalation study of navitoclax followed by a phase II study.

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

      After completion of study treatment, patients are followed up for 30 days and then every 12
      weeks thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (navitoclax, vistusertib)ExperimentalPatients receive navitoclax PO QD and vistusertib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Navitoclax
  • Vistusertib

Eligibility Criteria

        Inclusion Criteria:

          -  PHASE 1 SPECIFIC ELIGIBILITY CRITERIA

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

          -  PHASE 2 SPECIFIC ELIGIBILITY CRITERIA

          -  Patients must have histologically or cytologically confirmed small cell lung cancer
             whose disease has relapsed or progressed after >= 1 prior therapy, one of which must
             have been a platinum doublet; pathology confirmation must be done at Sidney Kimmel
             Comprehensive Cancer Center (SKCCC) or at the local participating site

          -  Patients must have measurable disease, defined as at least one lesion that can be
             accurately measured in at least one dimension (longest diameter to be recorded for
             non-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) by chest
             x-ray or as >= 10 mm (>= 1 cm) with computed tomography (CT) scan, magnetic resonance
             imaging (MRI), or calipers by clinical exam

          -  Subjects must be willing to undergo 2 sets of core needle biopsies (pre-treatment and
             on-treatment), if there are lesions amenable to biopsy; an optional core biopsy will
             be requested at progression

          -  GENERAL ELIGIBILITY CRITERIA

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)

          -  Life expectancy of greater than 12 weeks

          -  Leukocytes >= 3,000/mcL

          -  Absolute neutrophil count >= 1,500/mcL

          -  Hemoglobin >= 9.0 g/dL

          -  Platelets >= 100,000/mcL

          -  Activated partial thromboplastin time (aPTT), prothrombin time (PT) =< 1.2 x upper
             limit of normal (ULN)

          -  Total bilirubin =< 1.5 x ULN (patients with Gilbert's syndrome may have serum
             bilirubin > 1.5 ULN)

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 2.5 x institutional ULN if no demonstrable liver metastases or =< 5 x ULN in the
             presence of liver metastases

          -  Creatinine =< 1.5 x ULN and concurrent creatinine clearance (CrCl) >= 50 mL/min/1.73
             m^2 for patients with creatinine (Cr) > 1.5 x ULN

          -  Proteinuria < 1+ on dipstick testing (if 2+ seen on first test, retest >= 24 hours
             later)

          -  Patients with a history of central nervous system (CNS) metastases must have
             documentation of stable or improved status based on brain imaging for at least 2 weeks
             after completion of definitive treatment and within 2 weeks prior to first dose of
             study drug, off or on a stable dose of corticosteroids

          -  Patients must have completed chemotherapy, biological or radiotherapy >= 3 weeks prior
             to entering the study

          -  Patients must have recovered to =< grade 1 adverse events or to =< grade 2 alopecia
             and sensory neuropathy due to prior treatment

          -  Patients must be able to understand and the willingness to sign a written informed
             consent document

          -  Patients must be able to swallow pills

          -  The effects of navitoclax and vistusertib on the developing human fetus are unknown;
             for this reason, women of child-bearing potential and men must agree to use adequate
             contraception prior to study entry, for the duration of study participation, and up to
             90 days following completion of therapy; for women this should include one highly
             effective method of contraception and one barrier method as defined below

               -  Highly effective methods include:

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

                    -  Vasectomized partner;

                    -  Medroxyprogesterone acetate depot injection;

                    -  Placement of a copper-banded intrauterine device (IUD) or intrauterine
                       system (IUS);

                    -  Bilateral tubal ligation;

               -  Barrier methods include:

                    -  Condom;

                    -  Occlusive cap (e.g. diaphragm or cervical/vault caps) with spermicide

               -  Please note: use of other oral, injected or implanted hormonal methods of
                  contraception cannot be considered highly effective as it is currently unknown
                  whether vistusertib may reduce their effectiveness; periodic abstinence, the
                  rhythm method, and the withdrawal method are not acceptable methods of
                  contraception

               -  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

          -  Women of childbearing potential must have a negative urine pregnancy test within 7
             days prior to initiation of treatment, 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)

          -  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; men
             treated or enrolled on this protocol must also agree to use adequate contraception
             prior to the study, for the duration of study participation, and for 90 days after
             completion of navitoclax and/or vistusertib administration

        Exclusion Criteria:

          -  PHASE 2 SPECIFIC EXCLUSION CRITERIA

          -  Prior treatment with a TORC1, dual TORC1/2 inhibitor, or BCL-2/xL inhibitor

          -  Patients with active malignancies other than SCLC or patients with prior curatively
             treated malignancy at high risk of relapse during the study period with the exception
             of localized squamous or basal cell skin cancers

          -  PHASE 1 AND GENERAL EXCLUSION CRITERIA

          -  Major surgery within 21 days of starting protocol treatment

          -  Patients who are receiving any other investigational agents

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

          -  Patients receiving anticoagulation or anti-platelet therapy are excluded due to the
             risk of thrombocytopenia with navitoclax

               -  Excluded agents include heparin or low molecular weight heparin, warfarin,
                  clopidogrel, ibuprofen and other non-steroidal anti-inflammatory drugs (NSAIDS),
                  tirofiban, and other anticoagulants, drugs, or herbal supplements that affect
                  platelet function

               -  Administration of heparin to keep subject's infusion lines patent is allowed;
                  low-dose anticoagulation medications that are used to maintain the patency of a
                  central intravenous catheter are allowed

               -  Aspirin will not be allowed within 7 days prior to the first dose of navitoclax
                  or during navitoclax administration; however, subjects who have previously
                  received aspirin therapy for thrombosis prevention, may resume a low dose (i.e.,
                  maximum 100 mg once daily [QD]) of aspirin if platelet counts are stable (>=
                  50,000/mm3) through 6 weeks of navitoclax administration

               -  All decisions regarding treatment with aspirin therapy will be determined by the
                  investigator in conjunction with the medical monitor

          -  Patients with an underlying condition predisposing them to bleeding or currently
             exhibiting signs of clinically significant bleeding

          -  Patients with a recent history of non-chemotherapy-induced thrombocytopenic-associated
             bleeding within 1 year prior to the first dose of study drug

          -  Patients with a significant history of cardiovascular disease or procedures within the
             preceding 6 months (e.g., myocardial infarction [MI], coronary artery bypass graft
             placement, angioplasty, vascular stent, angina pectoris, ventricular arrhythmias
             requiring continuous therapy, congestive heart failure New York Heart Association
             [NYHA] grade >= 2, thrombotic or thromboembolic event)

          -  Any of the following cardiac criteria:

               -  Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470
                  msec obtained from 3 electrocardiograms

               -  Congenital or family history of long or short QT syndrome, Brugada syndrome,
                  known history of QTc prolongation or torsades de pointes within 12 months of
                  entering the study

               -  Abnormal echocardiogram at baseline (left ventricular ejection fraction [LVEF] <
                  40% and shortening fraction [SF] < 15%)

          -  Drugs which have an increased risk for QTc prolongation should be avoided

          -  Patients with uncontrolled type 1 or type 2 diabetes. Vistusertib belongs to a class
             of drugs that causes hyperglycemia. In order to assess toxicity, patients with an
             elevated risk of hyperglycemia should be excluded from study

          -  Patients currently receiving medications or herbal supplements of the classes below
             are ineligible; patients are eligible if they stop use of these compounds at least 1
             week prior to receiving any treatment on this protocol

               -  Potent inhibitors or inducers of CYP3A4 /5 (CYP3A4 inhibitors such as
                  ketoconazole and clarithromycin are not allowed 7 days prior to the first dose of
                  navitoclax and during navitoclax administration)

               -  Strong or moderate inhibitors of Pgp or BRCP1

               -  Sensitive substrates of CYP2C9 (i.e. phenytoin and warfarin)

               -  Substrates of certain drug transporters (OATP1B1, OATP1B3, MATE1 or MATE2K)

          -  Pregnant women are excluded from this study because navitoclax and vistusertib have
             the potential for teratogenic or abortifacient effects; because there is an unknown
             but potential risk for adverse events in nursing infants secondary to treatment of the
             mother with navitoclax and vistusertib breastfeeding should be discontinued if the
             mother is treated with navitoclax and vistusertib

          -  Patients positive for human immunodeficiency virus (HIV) are not excluded from this
             study, but HIV-positive patients must have:

               -  A stable regimen of highly active anti-retroviral therapy (HAART) that does not
                  include strong or moderate CYP3A4 inducers or inhibitors

               -  No requirement for concurrent antibiotics or antifungal agents for the prevention
                  of opportunistic infections

               -  A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standard
                  polymerase chain reaction (PCR)-based test

          -  Any hematopoietic growth factors (e.g., filgrastim [granulocyte colony-stimulating
             factor; G-CSF], sargramostim [granulocyte-macrophage colony-stimulating factor;
             GM-CSF]) within 14 days prior to receiving study treatment

          -  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

          -  Patients who have received a live, attenuated vaccines within 4 weeks of first dose of
             drug
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse events (Phase I)
Time Frame:Up to 30 days after last treatment
Safety Issue:
Description:Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 4.0. Toxicities will be tabulated by type and grade for all doses and presented using frequencies and percentages based on the NCI CTCAE v 4.0. The proportion of dose limiting toxicities at each dose level will be reported with exact binomial 95% confidence intervals. All patients who receive at least 1 dose of both study drugs, regardless of their eligibility for the study, will be evaluable for toxicity.

Secondary Outcome Measures

Measure:Occurrence of a bi-directional pharmacokinetic (PK) interaction (Phase I)
Time Frame:Up to 1.5 years
Safety Issue:
Description:Descriptive statistics will be provided for selected PK, and pharmacodynamic data by dose and time as appropriate. Descriptive statistics on continuous data will include means, medians, standard deviations, and ranges, while categorical data will be summarized using frequency counts and percentages. Graphical summaries of the data may be presented.
Measure:Incidence of adverse events (Phase II)
Time Frame:Up to 1.5 years
Safety Issue:
Description:Graded by NCI CTCAE v 4.0. The proportion of toxicities by type and grade in the phase 2 study will be reported with exact binomial 95% confidence intervals.
Measure:Progression free survival (PFS) (Phase II)
Time Frame:Up to 1.5 years
Safety Issue:
Description:Based on RECIST 1.1. Standard life table methods will be used to analyze PFS. We will report the one-year and median PFS with 95% confidence intervals.
Measure:Overall survival (OS) (Phase II)
Time Frame:Up to 1.5 years
Safety Issue:
Description:Based on RECIST 1.1. Standard life table methods will be used to analyze OS. We will report the one-year and median OS with 95% confidence intervals.
Measure:Disease control rate (Phase II)
Time Frame:Up to 1.5 years
Safety Issue:
Description:Based on RECIST 1.1. The proportion of patients achieving disease control will be reported with exact 95% binomial confidence intervals.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

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