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

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ClinicalTrials.gov Identifier: NCT03366103
Recruitment Status : Recruiting
First Posted : December 8, 2017
Last Update Posted : October 29, 2018
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
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. 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 in treating patients with small cell lung cancer and solid tumors.

Condition or disease Intervention/treatment Phase
Metastatic Malignant Solid Neoplasm Recurrent Malignant Solid Neoplasm Recurrent Small Cell Lung Carcinoma Stage III Small Cell Lung Carcinoma AJCC v7 Stage IIIA Small Cell Lung Carcinoma AJCC v7 Stage IIIB Small Cell Lung Carcinoma AJCC v7 Stage IV Small Cell Lung Carcinoma AJCC v7 Unresectable Solid Neoplasm Other: Laboratory Biomarker Analysis Biological: Navitoclax Other: Pharmacological Study Drug: Vistusertib Phase 1 Phase 2

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)

TERTIARY 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. Courses 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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 79 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 1/2 Study of Navitoclax Plus Vistusertib in Patients With Relapsed Small Cell Lung Cancer (SCLC) and Other Solid Tumors
Actual Study Start Date : November 29, 2017
Estimated Primary Completion Date : May 31, 2020
Estimated Study Completion Date : May 31, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lung Cancer

Arm Intervention/treatment
Experimental: Treatment (navitoclax, vistusertib)
Patients receive navitoclax PO QD and vistusertib PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Other: Laboratory Biomarker Analysis
Correlative studies

Biological: Navitoclax
Given PO
Other Names:
  • A-855071.0
  • ABT-263
  • BcI-2 Family Protein Inhibitor ABT-263

Other: Pharmacological Study
Correlative studies

Drug: Vistusertib
Given PO
Other Names:
  • AZD 2014
  • AZD-2014
  • AZD2014




Primary Outcome Measures :
  1. Incidence of adverse events graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 4.0 (Phase I) [ Time Frame: Up to 30 days after last treatment ]
    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 (DLTs) 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.

  2. Overall response rate (ORR) defined as Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 partial response (PR) or complete response (CR), of the combination in patients with recurrent small cell lung cancer (SCLC) (Phase II) [ Time Frame: Up to 1.5 years ]
    The ORR will be reported with its corresponding 95% confidence interval.


Secondary Outcome Measures :
  1. Occurrence of a bi-directional pharmacokinetic (PK) interaction (Phase I) [ Time Frame: Up to 1.5 years ]
    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.

  2. Incidence of adverse events assessed by NCI CTCAE v4.0 (Phase II) [ Time Frame: Up to 1.5 years ]
    The proportion of toxicities by type and grade in the phase 2 study will be reported with exact binomial 95% confidence intervals.

  3. Progression free survival (PFS) based on RECIST 1.1 (Phase II) [ Time Frame: Up to 1.5 years ]
    Standard life table methods will be used to analyze PFS. We will report the one-year and median PFS with 95% confidence intervals.

  4. Overall survival (OS) based on RECIST 1.1 (Phase II) [ Time Frame: Up to 1.5 years ]
    Standard life table methods will be used to analyze OS. We will report the one-year and median OS with 95% confidence intervals.

  5. Disease control rate based on RECIST 1.1 (Phase II) [ Time Frame: Up to 1.5 years ]
    The proportion of patients achieving disease control will be reported with exact 95% binomial confidence intervals.


Other Outcome Measures:
  1. Change in p4EBP1 expression [ Time Frame: Baseline up to 1.5 years ]
    Descriptive statistics and box plots with jittered data points will be used to visualize all raw data. Will be assessed with paired t-tests.

  2. Change in ratio p4EBP1/4EBP1 [ Time Frame: Baseline up to 1.5 years ]
    Descriptive statistics and box plots with jittered data points will be used to visualize all raw data. Will be assessed with paired t-tests.

  3. Change in ratio pS6/S6 [ Time Frame: Baseline up to 1.5 years ]
    Descriptive statistics and box plots with jittered data points will be used to visualize all raw data. Will be assessed with paired t-tests.

  4. Change in BAX and MCl-1 expression [ Time Frame: Baseline up to 1.5 years ]
    Descriptive statistics and box plots with jittered data points will be used to visualize all raw data. Will be assessed with paired t-tests.

  5. Pharmacodynamic parameters [ Time Frame: Up to 1.5 years ]
    Exploratory correlative studies with pharmacodynamic (biological endpoints, toxicity and efficacy) will be analyzed using nonparametric statistics.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • PHASE 1 SPECIFIC ELIGIBILITY CRITERIA
  • 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
  • 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
  • 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; 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; 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03366103


Locations
United States, Maryland
Johns Hopkins University/Sidney Kimmel Cancer Center Recruiting
Baltimore, Maryland, United States, 21287
Contact: Site Public Contact    410-955-8804    jhcccro@jhmi.edu   
Principal Investigator: Christine L. Hann         
United States, Massachusetts
Massachusetts General Hospital Cancer Center Recruiting
Boston, Massachusetts, United States, 02114
Contact: Site Public Contact    877-726-5130      
Principal Investigator: Anna F. Farago         
Brigham and Women's Hospital Recruiting
Boston, Massachusetts, United States, 02115
Contact: Site Public Contact    888-823-5923    ctsucontact@westat.com   
Principal Investigator: Anna F. Farago         
Beth Israel Deaconess Medical Center Recruiting
Boston, Massachusetts, United States, 02215
Contact: Site Public Contact    617-667-9925      
Principal Investigator: Anna F. Farago         
Dana-Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Contact: Site Public Contact    877-442-3324      
Principal Investigator: Anna F. Farago         
United States, New Jersey
Memorial Sloan Kettering Basking Ridge Recruiting
Basking Ridge, New Jersey, United States, 07920
Contact: Site Public Contact    212-639-7592      
Principal Investigator: Wei-Chu V. Lai         
Memorial Sloan Kettering Monmouth Recruiting
Middletown, New Jersey, United States, 07748
Contact: Site Public Contact    212-639-7592      
Principal Investigator: Wei-Chu V. Lai         
United States, New York
Memorial Sloan Kettering Commack Recruiting
Commack, New York, United States, 11725
Contact: Site Public Contact    212-639-7592      
Principal Investigator: Wei-Chu V. Lai         
Memorial Sloan Kettering Westchester Recruiting
Harrison, New York, United States, 10604
Contact: Site Public Contact    212-639-7592      
Principal Investigator: Wei-Chu V. Lai         
Memorial Sloan Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Site Public Contact    212-639-7592      
Principal Investigator: Wei-Chu V. Lai         
Memorial Sloan Kettering Rockville Centre Recruiting
Rockville Centre, New York, United States, 11570
Contact: Site Public Contact    212-639-7592      
Principal Investigator: Wei-Chu V. Lai         
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Christine Hann JHU Sidney Kimmel Comprehensive Cancer Center LAO

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03366103     History of Changes
Other Study ID Numbers: NCI-2017-00037
NCI-2017-00037 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
ETCTN10070
10070 ( Other Identifier: JHU Sidney Kimmel Comprehensive Cancer Center LAO )
10070 ( Other Identifier: CTEP )
UM1CA186691 ( U.S. NIH Grant/Contract )
First Posted: December 8, 2017    Key Record Dates
Last Update Posted: October 29, 2018
Last Verified: August 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:
Carcinoma
Neoplasms
Small Cell Lung Carcinoma
Lung Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Carcinoma, Bronchogenic
Bronchial Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Navitoclax
Antineoplastic Agents