Obatoclax Mesylate and Topotecan Hydrochloride in Treating Patients With Relapsed or Refractory Small Cell Lung Cancer or Advanced Solid Tumors

Phase I/II Study of Obatoclax Mesylate (GX15-070MS), a Bcl-2 Antagonist, Plus Topotecan in Relapsed Small Cell Lung Carcinoma

This phase I/II trial is studying the side effects and best dose of obatoclax mesylate when given together with topotecan hydrochloride and to see how well they work in treating patients with relapsed or refractory small cell lung cancer or advanced solid tumors. Obatoclax mesylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as topotecan hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving obatoclax mesylate together with topotecan hydrochloride may help kill more tumor cells

Study Overview

• Status: Completed
• Conditions: Unspecified Adult Solid Tumor, Protocol Specific; Recurrent Small Cell Lung Cancer
• Intervention / Treatment: Other: laboratory biomarker analysis; Drug: topotecan hydrochloride; Drug: obatoclax mesylate

Detailed Description

PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose, recommended phase II dose, and toxicity profile of obatoclax mesylate when administered with topotecan hydrochloride in patients with advanced solid tumors. (Phase I) II. Determine the response rate in patients with relapsed or refractory small cell lung cancer treated with obatoclax mesylate and topotecan hydrochloride. (Phase II)

SECONDARY OBJECTIVES:

I. Evaluate the expression of pro- and anti-apoptotic proteins which may correlate with obatoclax mesylate sensitivity or resistance.

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

PHASE I (solid tumor): Patients receive obatoclax mesylate IV over 3 hours on day 1 OR days 1 and 3 and topotecan hydrochloride IV over 30 minutes on days 1-5. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.

PHASE II (small cell lung cancer): Patients receive obatoclax mesylate and topotecan hydrochloride at the recommended phase II dose (RPTD) determined in phase I. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.

Tumor tissue samples from patients with small cell lung cancer may be collected at baseline for correlative studies. Tissue samples are analyzed for biomarkers and protein expression of Bcl-2, Bcl-Xl, MCL-1, Bax, Bad, c-Myc, L-Myc, and N-Myc by immunohistochemistry.

After completion of study treatment, patients are followed for 30 days.

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21231
      • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histologically or cytologically confirmed diagnosis of 1 of the following:

  • Advanced solid tumor (phase I)

    • Topotecan hydrochloride must be an appropriate treatment for this cancer

  • Small cell lung cancer (SCLC) (phase II)

    • Progressed after one prior platinum-based chemotherapy regimen
    • Pathology materials (tumor tissue) will be used for correlative studies, if available

• No progressive brain metastases

  • Treated brain metastases allowed provided patient is neurologically stable and does not require steroids
• No leptomeningeal involvement
• ECOG performance status (PS) 0-1 OR Karnofsky PS 70-100%
• Leukocytes ≥ 3,000/mcL
• Absolute neutrophil count ≥ 1,500/mcL
• Platelet count ≥ 100,000/mcL
• Total bilirubin normal
• AST and ALT ≤ 2.5 times upper limit of normal
• Creatinine normal OR creatinine clearance ≥ 60 mL/min
• Not pregnant or nursing
• Fertile patients must use effective double barrier method of contraception during and for 3 months after completion of study therapy
• At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C) and recovered
• At least 4 weeks since prior radiotherapy and recovered
• No concurrent combination antiretroviral therapy for HIV-positive patients
• No other concurrent investigational agents or anticancer therapy

Exclusion Criteria:

• History of allergic reactions attributed to compounds of similar chemical or biological composition to obatoclax mesylate or topotecan hydrochloride (e.g., irinotecan)

• Concurrent uncontrolled illness including, but not limited to, any of the following:

  • Ongoing or active infection
  • Symptomatic congestive heart failure
  • Unstable angina pectoris
  • Cardiac arrhythmia
  • Psychiatric illness or social situations that would limit compliance with study requirements
• History of seizure disorder or other neurological dysfunction (except peripheral neuropathy)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment (enzyme inhibitor therapy and chemotherapy); Patients receive obatoclax mesylate IV over 3 hours on day 1 OR days 1 and 3 and topotecan hydrochloride IV over 30 minutes on days 1-5. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity	Other: laboratory biomarker analysis; Correlative studies; Drug: topotecan hydrochloride; Given IV; Other Names: Hycamtin; SKF S-104864-A; hycamptamine; TOPO; Drug: obatoclax mesylate; Given IV; Other Names: GX15-070MS

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate (Phase II)	Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR)=CR +PR	Every 6 weeks, assessed up to 30 days

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Lee Krug, Memorial Sloan Kettering Cancer Center

Publications and helpful links

General Publications

• Paik PK, Rudin CM, Pietanza MC, Brown A, Rizvi NA, Takebe N, Travis W, James L, Ginsberg MS, Juergens R, Markus S, Tyson L, Subzwari S, Kris MG, Krug LM. A phase II study of obatoclax mesylate, a Bcl-2 antagonist, plus topotecan in relapsed small cell lung cancer. Lung Cancer. 2011 Dec;74(3):481-5. doi: 10.1016/j.lungcan.2011.05.005. Epub 2011 May 26.

Study record dates

Study Major Dates

• Study Start: August 1, 2007
• Primary Completion (Actual): August 1, 2010
• Study Completion (Actual): August 1, 2010

Study Registration Dates

• First Submitted: August 24, 2007
• First Submitted That Met QC Criteria: August 24, 2007
• First Posted (Estimate): August 27, 2007

Study Record Updates

• Last Update Posted (Estimate): May 5, 2015
• Last Update Submitted That Met QC Criteria: April 14, 2015
• Last Verified: December 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Small Cell Lung Carcinoma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase Inhibitors; Topoisomerase I Inhibitors; Topotecan; Obatoclax
• Other Study ID Numbers: NCI-2009-00252; 07-082 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); CDR0000561779 (Registry Identifier: PDQ (Physician Data Query))