A Phase I/II Study of Dasatinib and Dacarbazine

This study has been completed.
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
H. Lee Moffitt Cancer Center and Research Institute
ClinicalTrials.gov Identifier:
NCT00597038
First received: January 8, 2008
Last updated: November 21, 2013
Last verified: May 2012
  Purpose

The purpose of this study is to:

Phase I Objectives:

  • Find the most tolerated dose to use for Phase II
  • Collect information on how the body responds to this combination of study drug

Phase II Objectives:

  • To determine the overall response of participants using this combination of study drug

The expression of proto-oncogene tyrosine-protein kinase (Src), a substance present in a significant proportion of melanomas plays a role in the growth, multiplying, and dividing of cancer cells. Melanoma cells appear to be sensitive to these agents that block the action of Src in concentrations that can be achieved in patients. We suggest that Src inhibitors (such as Dasatinib) may be a good choice for treatment of melanoma in combination with Dacarbazine (a chemotherapy drug that can cause the shrinkage of melanomas). We wish to to evaluate the Src inhibitor Dasatinib in combination with the chemotherapy drug Dacarbazine. The novel oral Src inhibitor Dasatinib may be able to increase the effectiveness of chemotherapy for melanoma compared to chemotherapy alone. Dacarbazine is a standard treatment for melanoma currently. The effectiveness of this chemotherapy drug may be increased by combination with Dasatinib. Dacarbazine has been approved by the US Food and Drug Administration (FDA) for treating melanoma; Dasatinib has been approved by the FDA to treat leukemia, but it has not been approved alone or in combination with Dacarbazine to treat melanoma.


Condition Intervention Phase
Metastatic Melanoma
Drug: Dasatinib and Dacarbazine (DTIC)
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I/II Study of Dasatinib and Dacarbazine in Patients With Metastatic Melanoma

Resource links provided by NLM:


Further study details as provided by H. Lee Moffitt Cancer Center and Research Institute:

Primary Outcome Measures:
  • Recommended Phase II Dose [ Time Frame: 1 Year 3 Months ] [ Designated as safety issue: No ]
    To determine the maximum tolerated dose of dasatinib twice a day when given with dacarbazine. Adverse events were graded using Common Terminology Criteria for Adverse Events version 3.0. Dose-limiting toxicities are defined as any grade 4 haematological toxicity (except asymptomatic grade 4 neutropenia for =/< 7 days); prolonged grade 3 or 4 thrombocytopenia (47 days) or thrombocytopenia associated with bleeding, requiring platelet transfusion; any grade 3 or 4 nonhaematological toxicity despite optimal supportive care; any toxicity considered unacceptable by the study principal investigator.

  • Phase II - Number of Participants With Overall Response (OR) [ Time Frame: 1 Year 6 Months ] [ Designated as safety issue: No ]
    Phase II - To determine the overall response rate (ORR) of the combination of dasatinib and DTIC by the Response Evaluation Criteria in Solid Tumors (RECIST v1.0). Tumor assessments were made at baseline and at the end of every second cycle (i.e. every 6 weeks). Partial and complete responses were defined by the best treatment response achieved.


Secondary Outcome Measures:
  • Number of Participants With Progression Free Survival (PFS) at 6 Months [ Time Frame: 6 Months ] [ Designated as safety issue: No ]
    Phase II - PFS Rate in patients receiving dasatinib 70 mg orally (PO) twice a day (BID). Tumor assessments were made at baseline and at the end of every second cycle (i.e. every 6 weeks). Partial and complete responses were defined by the best treatment response achieved. Stable disease was defined as maintenance of the sum of lesions diameters between a 30% reduction and a 20% increase of overall tumour size over 12 weeks or longer.

  • Number of Participants With 12 Month Overall Survival (OS) [ Time Frame: 12 Months ] [ Designated as safety issue: No ]
    Phase II - To determine Overall Survival of patients treated with the combination of dasatinib and DTIC at 12 months.


Enrollment: 50
Study Start Date: November 2007
Study Completion Date: September 2011
Primary Completion Date: September 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Phase I Dose Escalation
Dasatinib and Dacarbazine (DTIC). The first cohort was a dasatinib dose of 50 mg by mouth (PO) twice a day (BID) given days 2-19 with DTIC given at a dose of 800 mg/m2 once every 3 weeks. The dose escalation was continued until MTD and a recommended Phase II dose was established.
Drug: Dasatinib and Dacarbazine (DTIC)

Arm A/ Phase I Potential Dose Levels.

Dose Level -1: Dasatinib 40 mg; DTIC 600 mg/m^2. Dose Level 1: Dasatinib 50 mg; DTIC 800 mg/m^2. Dose Level 2: Dasatinib 70 mg; DTIC 800 mg/m^2. Dose Level 3: Dasatinib 70 mg; DTIC 1000 mg/m^2.

Arm B/Phase II Potential Dose Levels.

MTD1: Dasatinib 70 mg; DTIC 1000 mg/m^2. MTD2: Dasatinib 70 mg; DTIC 800 mg/m^2. MTD3: Dasatinib 100 mg: DTIC 1000 mg/m^2.

Other Names:
  • Sprycel (Dasatinib)
  • DTIC (Dacarbazine)
Experimental: Phase II Dose Treatment
Dasatinib and Dacarbazine (DTIC). The recommended phase II dose was dasatinib 70 mg BID with dacarbazine 800 mgm^2.
Drug: Dasatinib and Dacarbazine (DTIC)

Arm A/ Phase I Potential Dose Levels.

Dose Level -1: Dasatinib 40 mg; DTIC 600 mg/m^2. Dose Level 1: Dasatinib 50 mg; DTIC 800 mg/m^2. Dose Level 2: Dasatinib 70 mg; DTIC 800 mg/m^2. Dose Level 3: Dasatinib 70 mg; DTIC 1000 mg/m^2.

Arm B/Phase II Potential Dose Levels.

MTD1: Dasatinib 70 mg; DTIC 1000 mg/m^2. MTD2: Dasatinib 70 mg; DTIC 800 mg/m^2. MTD3: Dasatinib 100 mg: DTIC 1000 mg/m^2.

Other Names:
  • Sprycel (Dasatinib)
  • DTIC (Dacarbazine)

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically or cytologically proven melanoma with Stage IV or unresectable stage III disease
  • Resolution of all acute toxic effects of prior radiotherapy or surgical procedures to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 grade ≤1.
  • Adequate organ function as defined by the following criteria:

    • Serum aspartate transaminase (AST); serum glutamic oxaloacetic transaminase (SGOT) and serum alanine transaminase (ALT); serum glutamic pyruvic transaminase (SGPT) ≤2.5 x local laboratory upper limit of normal (ULN), or AST and ALT less than or equal to 5 x ULN if liver function abnormalities are due to underlying malignancy
    • Total serum bilirubin ≤1.5 x ULN
    • Absolute neutrophil count (ANC) ≥1500/µL
    • Platelets ≥100,000/µL
    • Hemoglobin ≥9.0 g/dL (may be transfused or erythropoietin treated)
    • Serum calcium ≤12.0 mg/dL
    • Serum creatinine ≤1.5 x ULN
  • Patients with CNS metastasis must have had either; a) resected central nervous system (CNS) metastasis without evidence of recurrence for >12 weeks; b) Brain metastasis treated by stereotactic radiosurgery without evidence of recurrence or progression for 12 weeks; Or, c) Multiple brain lesions treated with whole-brain radiation therapy (WBRT) with stable disease off corticosteroids for at least 12 weeks prior to start of therapy; and, d)Without any evidence of leptomeningeal disease. Patients must be neurologically intact.
  • May have previous adjuvant therapy with interferon, vaccines or therapy with IL-2 or GM-CSF
  • Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria is required in the Phase II portion of the trial. In the phase I part of the trial patients with evaluable but not measurable disease may be allowed with the permission of the Principal Investigator (PI)
  • Eastern Cooperative Oncology Group (ECOG) PS 0-2

Exclusion Criteria:

  • Major surgery or radiation therapy within 4 weeks of starting the study treatment.
  • NCI CTCAE grade 2 or greater hemorrhage within 4 weeks of starting the study treatment.
  • History of or known carcinomatous meningitis, or evidence of symptomatic leptomeningeal disease on screening CT or MRI scan.
  • Any of the following within the 6 months prior to study drug administration: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, or pulmonary embolism.
  • Ongoing cardiac dysrhythmias of NCI CTCAE grade ≥2.
  • QTc >470 msec on baseline EKG.
  • Hypertension that cannot be controlled by medications (>150/100 mm Hg despite optimal medical therapy).
  • Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness or other active infection
  • Ongoing treatment with therapeutic doses of warfarin (low dose warfarin up to 2 mg orally (po) daily for thromboembolism prophylaxis is allowed).
  • Pregnancy or breastfeeding. Female patients must be surgically sterile or be postmenopausal, or must agree to use effective contraception during the period of therapy. All female patients with reproductive potential must have a negative pregnancy test (serum or urine) prior to enrollment. Male patients must be surgically sterile or must agree to use effective contraception during the period of therapy. The definition of effective contraception will be based on the judgment of the principal investigator or a designated associate.
  • Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the subject inappropriate for entry into this study.
  • May not have had previous treatment with a Dacarbazine (DTIC) or temozolomide based chemotherapy regimen. In the Phase II part of the trial patients may not have had treatment with any chemotherapy regimen
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00597038

Locations
United States, California
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco
San Francisco, California, United States, 94115
United States, Florida
H. Lee Moffitt Cancer Center & Research Institute
Tampa, Florida, United States, 33612
Sponsors and Collaborators
H. Lee Moffitt Cancer Center and Research Institute
Bristol-Myers Squibb
Investigators
Principal Investigator: Jeffrey Weber, M.D.. Ph.D. H. Lee Moffitt Cancer Center and Research Institute
Study Chair: Adil Daud, M.D. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco
  More Information

Additional Information:
No publications provided

Responsible Party: H. Lee Moffitt Cancer Center and Research Institute
ClinicalTrials.gov Identifier: NCT00597038     History of Changes
Other Study ID Numbers: MCC-15256, 106128, CA180-092
Study First Received: January 8, 2008
Results First Received: May 22, 2012
Last Updated: November 21, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by H. Lee Moffitt Cancer Center and Research Institute:
Dasatinib
Dacarbazine

Additional relevant MeSH terms:
Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Dacarbazine
Dasatinib
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Protein Kinase Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on April 23, 2014