Imatinib Mesylate and Bevacizumab in Treating Patients With Advanced Melanoma or Other Advanced Cancers

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00074308
• Collaborator: (none)
• Enrollment: 40
• Location: 1
• Arm: 1
• Duration (Months): 69
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

Phase II trial to study the effectiveness of combining imatinib mesylate with bevacizumab in treating patients who have advanced melanoma or other metastatic or unresectable cancer. Imatinib mesylate may stop the growth of tumor cells by blocking the enzymes necessary for their growth. Bevacizumab may stop the growth of tumor cells by stopping blood flow to the tumor. Combining imatinib mesylate with bevacizumab may kill more tumor cells

Condition or Disease	Intervention/Treatment	Phase
Recurrent Melanoma; Stage III Melanoma; Stage IV Melanoma; Unspecified Adult Solid Tumor, Protocol Specific	Drug: imatinib mesylate; Biological: bevacizumab; Other: pharmacological study; Other: laboratory biomarker analysis	Phase 1/Phase 2

Detailed Description

OBJECTIVES:

1. Determine the tolerability, maximum tolerated dose, and lowest biologically active dose of imatinib mesylate and bevacizumab in patients with advanced melanoma or other advanced cancers.

2. Determine the response rate, time to progression, and survival of patients treated with this regimen.

3. Correlate clinical activity with inhibition of platelet-derived growth factor receptor beta, vascular endothelial growth factor receptor, flt-1, and markers of angiogenesis in patients treated with this regimen.

4. Correlate clinical activity with alterations in tumor perfusion as assessed by dynamic contrast-enhanced MRI and Doppler ultrasound in patients treated with this regimen.

5. Correlate toxicity, clinical activity, and correlative endpoints with the steady-stage plasma concentration of imatinib mesylate in patients treated with this regimen.

OUTLINE: This is a dose-escalation, open-label study.

PHASE I (closed to accrual as of 8/23/04): Patients receive oral imatinib mesylate once or twice daily on days 1-28 and bevacizumab IV over 30-90 minutes on days 1 and 14. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of imatinib mesylate and bevacizumab until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

PHASE II: Patients receive imatinib mesylate and bevacizumab as in phase I at the MTD.

Study Design

• Study Type: Interventional
• Actual Enrollment: 40 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II Study Of Imatinib Mesylate And Bevacizumab In Patients With Advanced Melanoma And Other Advanced Cancers
• Study Start Date: Oct 1, 2003
• Actual Primary Completion Date: Jul 1, 2009
• Actual Study Completion Date: Jul 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I Patients receive oral imatinib mesylate once or twice daily on days 1-28 and bevacizumab IV over 30-90 minutes on days 1 and 14. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Drug: imatinib mesylate; Given orally; Other Names: CGP 57148 Gleevec Glivec ; Biological: bevacizumab; Given IV; Other Names: anti-VEGF humanized monoclonal antibody anti-VEGF monoclonal antibody Avastin rhuMAb VEGF ; Other: pharmacological study; Correlative studies; Other Names: pharmacological studies ; Other: laboratory biomarker analysis; Correlative studies

Outcome Measures

Primary Outcome Measures

1. MTD, Defined as One Dose Level Below the Dose That Induced DLT in at Least One Third of Patients at a Dose Level, Graded According to NCI CTCAE Version 3.0 (Phase I) [Up to 28 days]

2. Progression-free Survival at 16 Weeks (Phase II) [16 weeks]

   Progression Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.

Secondary Outcome Measures

1. Response Rate at 8 Weeks, Evaluated Using RECIST (Phase II) [8 weeks]

   Response and progression was evaluated in this study using Response Evaluation Criteria in Solid Tumors (RECIST). Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD.

2. Overall Survival (Phase II) [Up to 6 years]

   Kaplan-Meier estimates of overall survival and 95% confidence intervals will be calculated.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

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

• Metastatic or unresectable malignancy for which standard curative or palliative measures do not exist or are no longer effective (phase I) (phase I study closed to accrual as of 8/23/04)

• Melanoma (phase I and II)

• Measurable disease (phase II)

• No history or clinical evidence of CNS disease, including primary brain tumor or brain metastases

• Performance status - ECOG 0-1

• More than 3 months

• WBC at least 3,000/mm^3

• Absolute granulocyte count at least 1,500/mm^3

• Platelet count at least 100,000/mm^3

• No history of bleeding diathesis or coagulopathy

• Bilirubin no greater than 1.5 times upper limit of normal (ULN)

• AST and ALT no greater than 2.5 times ULN

• INR no greater than 1.5

• APTT normal

• Creatinine no greater than 2.0 times ULN

• Creatinine clearance at least 40 mL/min

• No proteinuria

• Urinary protein less than 500 mg/24 hours

• No history of stroke

• No uncontrolled hypertension within the past 6 months

• Blood pressure less than 150/100 mm Hg on a stable antihypertensive regimen

• None of the following within the past 6 months:

• Myocardial infarction

• Unstable angina

• New York Heart Association class II-IV congestive heart failure

• Serious cardiac arrhythmia requiring medication

• Grade II or greater peripheral vascular disease

• Transient ischemic attack

• Cerebrovascular accident

• Other arterial thromboembolic event

• Other clinically significant cardiovascular disease

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective barrier contraception during and for at least 3 months after study participation

• No seizures not controlled with standard medical therapy

• No prior allergic reactions attributed to Chinese hamster ovary cell products, other recombinant human antibodies, or compounds of similar chemical or biological composition to imatinib mesylate

• No serious, nonhealing wound, ulcer, or bone fracture

• No ongoing or active infection requiring parenteral antibiotics

• No significant traumatic injury within the past 28 days

• No psychiatric illness or social situation that would preclude study compliance

• No other concurrent uncontrolled illness

• More than 4 weeks since prior immunotherapy

• More than 8 weeks since prior monoclonal antibody therapy

• No concurrent prophylactic granulocyte or platelet colony-stimulating factors

• More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin)

• No more than 1 prior cytotoxic chemotherapy regimen for advanced disease (phase II)

• More than 4 weeks since prior radiotherapy

• More than 28 days since prior major surgical procedure or open biopsy

• Recovered from prior therapy

• No concurrent chronic daily aspirin (greater than 325 mg/day) or nonsteroidal anti-inflammatory drugs known to inhibit platelet function

• No recent or concurrent full-dose anticoagulants (except as required to maintain patency of preexisting permanent indwelling IV catheters) or thrombolytic agent

• No concurrent grapefruit juice

• No concurrent cytochrome P450 enzyme-inducing antiepileptic drugs (e.g., phenytoin, carbamazepine, or phenobarbital)

• No concurrent combination antiretroviral therapy for HIV-positive patients

• No other concurrent investigational or commercial agents or therapies directed at the malignancy

• No other concurrent investigational agents

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Abramson Cancer Center of The University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Keith Flaherty, Abramson Cancer Center of the University of Pennsylvania

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00074308
• Other Study ID Numbers: NCI-2012-02564; 03903; CDR0000343804
• First Posted: Dec 11, 2003
• Last Update Posted: Jun 20, 2018
• Last Verified: May 1, 2018

• Additional relevant MeSH terms: Melanoma; Bevacizumab; Antineoplastic Agents, Immunological; Imatinib Mesylate; Antibodies; Immunoglobulins; Antibodies, Monoclonal

Study Results

Participant Flow

Arm/Group Title	Phase 1 - Dose 1	Phase 1 Dose 2	Phase 1 Dose 3	Phase 1 Dose 4	Phase 2
Arm/Group Description	Bevacizumab (5 mg/kg) Imatinib (400 mg/day)	Bevacizumab (10 mg/kg) Imatinib (400 mg/day)	Bevacizumab (10 mg/kg) Imatinib (600 mg/day)	Bevacizumab (10 mg/kg) Imatinib (800 mg/day)	Bevacizumab (10 mg/kg) Imatinib (400 mg/day)
Period Title: Overall Study
STARTED	3	3	3	8	23
COMPLETED	3	3	3	8	23
NOT COMPLETED	0	0	0	0	0

Baseline Characteristics

Arm/Group Title	Phase 1	Phase 2	Total
Arm/Group Description	Patients receive oral imatinib mesylate once or twice daily (400-800 mg/day) on days 1-28 and bevacizumab IV (5-10mg/kg) over 30-90 minutes on days 1 and 14. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Patients receive oral imatinib mesylate once or twice daily (400 mg/day) on days 1-28 and bevacizumab IV (10mg/kg) over 30-90 minutes on days 1 and 14. Courses repeat every 28 days in the absence of disease progression or unacceptance toxicity.	Total of all reporting groups
Overall Participants	17	23	40
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	17 100%	23 100%	40 100%
>=65 years	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	4 23.5%	7 30.4%	11 27.5%
Male	13 76.5%	16 69.6%	29 72.5%
Region of Enrollment (Count of Participants)
United States	17 100%	23 100%	40 100%

Outcome Measures

1. Primary Outcome

Title	MTD, Defined as One Dose Level Below the Dose That Induced DLT in at Least One Third of Patients at a Dose Level, Graded According to NCI CTCAE Version 3.0 (Phase I)
Time Frame	Up to 28 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase 1 = Dose Escalation
Arm/Group Description	Patients receive oral imatinib mesylate once or twice daily on days 1-28 and bevacizumab IV over 30-90 minutes on days 1 and 14. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. imatinib mesylate: Given orally bevacizumab: Given IV pharmacological study: Correlative studies laboratory biomarker analysis: Correlative studies
Measure Participants	17
Number [dose level]	2

2. Primary Outcome

Title	Progression-free Survival at 16 Weeks (Phase II)
Description	Progression Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.
Time Frame	16 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase 2 = Dose Expansion
Arm/Group Description	Patients receive oral imatinib mesylate once or twice daily on days 1-28 and bevacizumab IV over 30-90 minutes on days 1 and 14. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. imatinib mesylate: Given orally bevacizumab: Given IV pharmacological study: Correlative studies laboratory biomarker analysis: Correlative studies
Measure Participants	23
Count of Participants [Participants]	8 47.1%

3. Secondary Outcome

Title	Response Rate at 8 Weeks, Evaluated Using RECIST (Phase II)
Description	Response and progression was evaluated in this study using Response Evaluation Criteria in Solid Tumors (RECIST). Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD.
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase 2 = Dose Expansion
Arm/Group Description	Patients receive oral imatinib mesylate once or twice daily on days 1-28 and bevacizumab IV over 30-90 minutes on days 1 and 14. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. imatinib mesylate: Given orally bevacizumab: Given IV pharmacological study: Correlative studies laboratory biomarker analysis: Correlative studies
Measure Participants	23
Count of Participants [Participants]	1 5.9%

4. Secondary Outcome

Title	Overall Survival (Phase II)
Description	Kaplan-Meier estimates of overall survival and 95% confidence intervals will be calculated.
Time Frame	Up to 6 years

Outcome Measure Data

Analysis Population Description

Data not collected

Arm/Group Title	Arm I
Arm/Group Description	Patients receive oral imatinib mesylate once or twice daily on days 1-28 and bevacizumab IV over 30-90 minutes on days 1 and 14. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. imatinib mesylate: Given orally bevacizumab: Given IV pharmacological study: Correlative studies laboratory biomarker analysis: Correlative studies
Measure Participants	0

Adverse Events

Time Frame	Grades 1 and 2 events are included as non-serious. Grade 3 and 4 events are included as serious
Arm/Group Title	Phase 1 - Dose 1		Phase 1 Dose 2		Phase 1 Dose 3		Phase 1 Dose 4		Phase 2
Arm/Group Description	Bevacizumab (5 mg/kg) Imatinib (400 mg/day)		Bevacizumab (10 mg/kg) Imatinib (400 mg/day)		Bevacizumab (10 mg/kg) Imatinib (600 mg/day)		Bevacizumab (10 mg/kg) Imatinib (800 mg/day)		Bevacizumab (10 mg/kg) Imatinib (400 mg/day)
All Cause Mortality
	Phase 1 - Dose 1		Phase 1 Dose 2		Phase 1 Dose 3		Phase 1 Dose 4		Phase 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		0/3 (0%)		0/3 (0%)		0/8 (0%)		2/23 (8.7%)
Serious Adverse Events
	Phase 1 - Dose 1		Phase 1 Dose 2		Phase 1 Dose 3		Phase 1 Dose 4		Phase 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/8 (12.5%)		1/23 (4.3%)
Blood and lymphatic system disorders
Blood and lympathic system disorders	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/8 (12.5%)	1	1/23 (4.3%)	1
Cardiac disorders
Hypertension	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/8 (0%)	0	0/23 (0%)	0
Gastrointestinal disorders
Abdominal Pain	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/8 (0%)	0	1/23 (4.3%)	1
Diarrhea	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/8 (12.5%)	1	0/23 (0%)	0
Nausea/vomiting	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/8 (12.5%)	1	0/23 (0%)	0
Renal and urinary disorders
Renal insufficiency	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/8 (12.5%)	1	0/23 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnea	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/8 (0%)	0	1/23 (4.3%)	1
Pneumonitis	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/8 (0%)	0	1/23 (4.3%)	1
Other (Not Including Serious) Adverse Events
	Phase 1 - Dose 1		Phase 1 Dose 2		Phase 1 Dose 3		Phase 1 Dose 4		Phase 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/8 (12.5%)		1/23 (4.3%)
Blood and lymphatic system disorders
Anemia	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/8 (12.5%)	1	1/23 (4.3%)	1
Leukopenia	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/8 (12.5%)	1	0/23 (0%)	0
Neutropenia	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/8 (12.5%)	1	1/23 (4.3%)	1
Thrombocytopenia	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/8 (12.5%)	1	1/23 (4.3%)	1
Cardiac disorders
Hypertension	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/8 (12.5%)	1	1/23 (4.3%)	1
Gastrointestinal disorders
Abdominal Pain	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/8 (12.5%)	1	1/23 (4.3%)	1
Constipation	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/8 (12.5%)	1	1/23 (4.3%)	1
Diarrhea	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/8 (12.5%)	1	0/23 (0%)	0
Gastrointestinal Bleeding	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/8 (12.5%)	1	0/23 (0%)	0
General disorders
Cough	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/8 (12.5%)	1	1/23 (4.3%)	1
Edema	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/8 (12.5%)	1	1/23 (4.3%)	1
Fatigue	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/8 (12.5%)	1	1/23 (4.3%)	1
Fever	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/8 (12.5%)	1	1/23 (4.3%)	1
Flushing	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/8 (12.5%)	1	1/23 (4.3%)	1
Nausea/vomiting	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/8 (12.5%)	1	1/23 (4.3%)	1
Weight gain	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/8 (12.5%)	1	1/23 (4.3%)	1
Weight loss	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/8 (12.5%)	1	0/23 (0%)	0
Musculoskeletal and connective tissue disorders
Myalgia	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/8 (12.5%)	1	1/23 (4.3%)	1
Psychiatric disorders
Anorexia	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/8 (12.5%)	1	1/23 (4.3%)	1
Renal and urinary disorders
Proteinuria	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/8 (12.5%)	1	1/23 (4.3%)	1
Renal insufficiency	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/8 (12.5%)	1	1/23 (4.3%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/8 (12.5%)	1	1/23 (4.3%)	1
Skin and subcutaneous tissue disorders
Rash	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/8 (12.5%)	1	1/23 (4.3%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.