Paclitaxel and Carboplatin or Temozolomide in Treating Patients With Stage IV Melanoma

• Sponsor: Mayo Clinic (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00568451
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 12
• Location: 1
• Arms: 4
• Duration (Months): 70
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. It is not yet known whether giving paclitaxel together with carboplatin is more effective than giving temozolomide alone in treating patients with melanoma.

PURPOSE: This phase II trial is studying the side effects and how well giving paclitaxel together with carboplatin or giving temozolomide alone works in treating patients with stage IV melanoma.

Condition or Disease	Intervention/Treatment	Phase
Melanoma (Skin)	Drug: carboplatin; Drug: paclitaxel; Drug: temozolomide	Phase 2

Detailed Description

OBJECTIVES:

• To assess the anti-tumor activity and toxicity profile of timed delivery of conventional paclitaxel and carboplatin (PC) in patients with stage IV melanoma who have received prior chemotherapy for their metastatic disease.

• To assess the anti-tumor activity and toxicity profile of timed delivery of conventional temozolomide (TMZ) chemotherapy in patients with stage IV melanoma who have received prior chemotherapy for their metastatic disease.

• To assess the anti-tumor activity and toxicity profile of timed delivery of conventional PC in patients with stage IV melanoma who have not received prior chemotherapy for their metastatic disease.

• To assess the anti-tumor activity and toxicity profile of timed delivery of conventional TMZ chemotherapy in patients with stage IV melanoma who have not received prior chemotherapy for their metastatic disease.

• To evaluate the changes of T-regulator cells, melanoma-specific functional parameters as a function of time in all four patient cohorts.

OUTLINE: Patients are stratified according to prior chemotherapy for metastatic disease (yes vs no) and scheduled chemotherapy regimen (paclitaxel and carboplatin vs temozolomide).

Beginning at the predicted day of C-reactive peptide (CRP) peak levels, patients receive paclitaxel IV and carboplatin IV on days 1, 8, and 15 OR oral temozolomide alone on days 1-5. Treatment repeats every 4 weeks in the absence of disease progression or unacceptable toxicity.

Patients undergo blood sample collection periodically for pharmacological studies. Samples are analyzed for CRP quantification via ELISA; presence and number of circulating blood T-regulator cells via immunophenotyping for CD4/CD25+ and CD4/fox-p3+ T cells; level of functional immunity against melanoma specific antigens (MART-1, tyrosinase, and gp100) and survivin in patients that are HLA-A2+ via intracellular staining; total number of cytotoxic T lymphocytes (CTLs) capable of reacting against melanoma targets via tetramer staining (Becton-Coulter); and quantification of interferon γ-producing, peptide-specific CTLs via multicolor conventional flow cytometry.

After completion of study treatment, patients are followed every 3 months for up to 2 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 12 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Releasing the Cancer Patient's Immune System From Down-regulation With Timed Delivery of Standard Chemotherapy
• Study Start Date: Jun 1, 2006
• Actual Primary Completion Date: May 1, 2009
• Actual Study Completion Date: Apr 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: PC (previously treated) Previously chemotherapy treated cohorts: Paclitaxel and Carboplatin (PC)	Drug: carboplatin; AUC=2 intravenously on days 1, 8 and 15. Re-treat every 4 weeks until progression, unacceptable toxicity, or refusal; Drug: paclitaxel; 100mg/m^2 intravenously on days 1, 8 and 15. Re-treat every 4 weeks until progression, unacceptable toxicity, or refusal; Other Names: Taxol
Experimental: PC (chemo naive) Chemotherapy-naive cohorts: Paclitaxel and Carboplatin (PC)	Drug: carboplatin; AUC=2 intravenously on days 1, 8 and 15. Re-treat every 4 weeks until progression, unacceptable toxicity, or refusal; Drug: paclitaxel; 100mg/m^2 intravenously on days 1, 8 and 15. Re-treat every 4 weeks until progression, unacceptable toxicity, or refusal; Other Names: Taxol
Experimental: TMZ (previously treated) Previously chemotherapy treated cohorts: Temozolomide (TMZ)	Drug: temozolomide; 150mg/m^2 at cycle 1, 200mg/m^2 at cycle 2 and beyond, orally on days 1-5. Re-treat every 4 weeks until progression, unacceptable toxicity, or refusal. One treatment cycle=four weeks; Other Names: Temodar
Experimental: TMZ (chemo naive) Chemotherapy-naive cohorts: Temozolomide (TMZ)	Drug: temozolomide; 150mg/m^2 at cycle 1, 200mg/m^2 at cycle 2 and beyond, orally on days 1-5. Re-treat every 4 weeks until progression, unacceptable toxicity, or refusal. One treatment cycle=four weeks; Other Names: Temodar

Outcome Measures

Primary Outcome Measures

1. Number of Participants With an Objective Tumor Status of Either a Complete Response(CR) or Partial Response (PR), According to RECIST (Response Evaluation Criteria in Solid Tumors) Criteria [Every other cycle of therapy (cycle=4 weeks) for the first 6 cycles of treatment]

   Response that was noted on 2 consecutive evaluations for at least 4 weeks apart. CR: Disappearance of all target lesions; PR: At least a 30 percent of decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD. Target lesions: All measurable lesions up to a maximum of 10 lesions representative of all involved organs.

Secondary Outcome Measures

1. Time to Disease Progression [up to 2 years]

   Time to disease progression was defined as the time from registration to documentation of disease progression. Disease progression was measured according to the RECIST criteria. Progression: At least a 20 percent increase in the sum of of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.

2. Survival Time [up to 2 years]

   Survival time was defined as the time from registration to death due to any cause.

3. Duration of Response for All Evaluable Patients Who Have Achieved an Objective Response [up to 2 years]

   Duration of response was defined as the date at which the participant's objective status was first noted to be either a Complete Response or Partial Response to the date the progression was documented.

4. Number of Participants Who Experienced Changes in Immunologic Profile (CD4/CD25+ Cells, CD4/Fox-p3+ T Cells) Within a Treatment [up to 2 years]

   Time series plot of the number of circulating cells will be constructed. The resulting plots will be visually inspected for trends within and between treatments. For each cell type, a point and an interval estimate of the number of participants (receiving a given treatment) who had at least a 2-fold increase in the number of circulating cells of that type will be constructed using the properties of the binomial distribution.

5. Number of Participants Who Experienced Changes in Immunologic Profile (MART-1, Tyrosinase, and gp100) Within a Treatment [up to 2 years]

   For those patients who are HLA-A2+, the maximum post-treatment levels of MART-1, tyrosinase, and gp100 will be determined. For each of these specific melanoma specific antigens, the number of participants (within a given treatment) who gained or maintained immunity based on the maximum post-treatment level of that specific melanoma specific antigen will be determined.

6. Number of Participants Who Experienced Changes in Immunologic Profile (IFNγ Producing Peptide Specific CTLs) Within a Treatment [up to 2 years]

   For each patient, a time series plot of the number of IFNγ producing peptide specific CTLs will be constructed. The resulting plots will be visually inspected for trends within and between treatments. A point and an interval estimate of the number of participants (receiving a given treatment) who had at least a 2-fold increase in the number of the number of IFNγ producing peptide specific CTLs will be constructed using the properties of the binomial distribution.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 120 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed metastatic melanoma

• Stage IV disease

• Progressive disease

• No known standard therapy that is potentially curative or proven capable of extending life expectancy exists

• Planning to undergo chemotherapy with paclitaxel and carboplatin OR temozolomide alone for progressive disease

• Measurable disease as defined by RECIST criteria

PATIENT CHARACTERISTICS:

• ECOG performance status 0-2

• Life expectancy ≥ 3 months

• ANC ≥ 1,500/mL

• Platelet count ≥ 100,000/mL

• Hemoglobin ≥ 9 g/dL

• Creatinine ≤ 2.5 x upper limit of normal (ULN)

• AST ≤ 3 x ULN

• Alkaline phosphatase ≤ 3.0 x ULN

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception during and for 1 month after completion of study therapy

• No uncontrolled intercurrent illness including, but not limited to, any of the following:

• Active infection

• NYHA class III or IV congestive heart failure

• No history of other malignancy within the past 5 years except for basal cell or squamous cell carcinoma of the skin treated with local resection only or carcinoma in situ of the cervix

• Willing to provide research blood samples

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics

• Recovered from prior therapy

• At least 4 weeks since prior radiotherapy

• At least 4 weeks since prior chemotherapy (patients who received chemotherapy in the metastatic setting)

• No prior chemotherapy treatment with agents similar to study drugs

• No prior chemotherapy in the metastatic setting (for chemo-naive patients)

• No concurrent enrollment in a different clinical study in which investigational procedures or agents are being used

• No other concurrent investigational agents

• No other concurrent chemotherapy or radiotherapy, including palliative radiotherapy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic Cancer Center	Rochester	Minnesota	United States	55905

Sponsors and Collaborators

• Mayo Clinic
• National Cancer Institute (NCI)

Investigators

• Study Chair: Svetomir Markovic, MD, PhD, Mayo Clinic

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Mayo Clinic
• ClinicalTrials.gov Identifier: NCT00568451
• Other Study ID Numbers: MC057F; P30CA015083; MC057F; 06-002547; NCI-2010-01794
• First Posted: Dec 6, 2007
• Last Update Posted: Dec 30, 2015
• Last Verified: Mar 1, 2014

• Keywords provided by Mayo Clinic: stage IV melanoma; recurrent melanoma
• Additional relevant MeSH terms: Melanoma; Paclitaxel; Carboplatin; Temozolomide

Study Results

Participant Flow

Recruitment Details	Twelve (12) participants with un-resectable stage IV malignant melanoma were enrolled in the study between June 2006 and November 2008 at Mayo Clinic Rochester.
Pre-assignment Detail	One patient canceled participation in the trial prior to starting Temozolomide therapy. This patient was excluded from all analysis.

Arm/Group Title	PC (Previously Treated)	PC (Chemo Naive)	TMZ (Previously Treated)	TMZ (Chemo Naive)
Arm/Group Description	Previously chemotherapy treated cohorts: Paclitaxel and Carboplatin (PC)	Chemotherapy-naive cohorts: Paclitaxel and Carboplatin (PC)	Previously chemotherapy treated cohorts: Temozolomide (TMZ)	Chemotherapy-naive cohorts: Temozolomide (TMZ)
Period Title: Overall Study
STARTED	0	0	2	9
COMPLETED	0	0	0	2
NOT COMPLETED	0	0	2	7

Baseline Characteristics

Arm/Group Title	PC (Previously Treated)	PC (Chemo Naive)	TMZ (Previously Treated)	TMZ (Chemo Naive)	Total
Arm/Group Description	Previously chemotherapy treated cohorts: Paclitaxel and Carboplatin (PC)	Chemotherapy-naive cohorts: Paclitaxel and Carboplatin (PC)	Previously chemotherapy treated cohorts: Temozolomide (TMZ)	Chemotherapy-naive cohorts: Temozolomide (TMZ)	Total of all reporting groups
Overall Participants	0	0	2	9	11
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61.5 (14.85)	63.3 (14.05)	62.4 (12.97)
Gender (participants) [Number]
Female	0 NaN	3 Infinity	3 150%
Male	2 Infinity	6 Infinity	8 400%
Region of Enrollment (participants) [Number]
United States	2 Infinity	9 Infinity	11 550%
M Stage (participants) [Number]
M1a (skin/subcutaneous tissue/lymph node only)	0 NaN	1 Infinity	1 50%
M1b (lung)	1 Infinity	3 Infinity	4 200%
M1c (other visceral sites)	1 Infinity	5 Infinity	6 300%
Number of Metastatic Sites (Sites) [Median (Full Range) ]
Median (Full Range) [Sites]	2	2	2

Outcome Measures

1. Primary Outcome

Title	Number of Participants With an Objective Tumor Status of Either a Complete Response(CR) or Partial Response (PR), According to RECIST (Response Evaluation Criteria in Solid Tumors) Criteria
Description	Response that was noted on 2 consecutive evaluations for at least 4 weeks apart. CR: Disappearance of all target lesions; PR: At least a 30 percent of decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD. Target lesions: All measurable lesions up to a maximum of 10 lesions representative of all involved organs.
Time Frame	Every other cycle of therapy (cycle=4 weeks) for the first 6 cycles of treatment

Outcome Measure Data

Analysis Population Description

All subjects enrolled, met the eligibility criteria who have signed a consent form and have begun their study treatment were evaluable for response.

Arm/Group Title	PC (Previously Treated)	PC (Chemo Naive)	TMZ (Previously Treated)	TMZ (Chemo Naive)
Arm/Group Description	Previously chemotherapy treated cohorts: Paclitaxel and Carboplatin (PC)	Chemotherapy-naive cohorts: Paclitaxel and Carboplatin (PC)	Previously chemotherapy treated cohorts: Temozolomide (TMZ)	Chemotherapy-naive cohorts: Temozolomide (TMZ)
Measure Participants	0	0	2	9
Number [participants]	0 NaN	2 Infinity

2. Secondary Outcome

Title	Time to Disease Progression
Description	Time to disease progression was defined as the time from registration to documentation of disease progression. Disease progression was measured according to the RECIST criteria. Progression: At least a 20 percent increase in the sum of 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	up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Overall
Arm/Group Description	TMZ (Previously Treated) and TMZ (Chemo Naive)
Measure Participants	11
Median (95% Confidence Interval) [Days]	74

3. Secondary Outcome

Title	Survival Time
Description	Survival time was defined as the time from registration to death due to any cause.
Time Frame	up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Overall
Arm/Group Description	TMZ (Previously Treated) and TMZ (Chemo Naive)
Measure Participants	11
Median (95% Confidence Interval) [Months]	12.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	PC (Previously Treated)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Median
	Estimated Value	12.5
	Confidence Interval	(1-Sided) 95%; 4.5 to
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Duration of Response for All Evaluable Patients Who Have Achieved an Objective Response
Description	Duration of response was defined as the date at which the participant's objective status was first noted to be either a Complete Response or Partial Response to the date the progression was documented.
Time Frame	up to 2 years

Outcome Measure Data

Analysis Population Description

Two complete tumor responses were documented. Both participants have since discontinued the study drug after 35 and 24 cycles respectively, and remain disease-free at 39 and 31.5 months since study entry. There is not enough participants to perform this analysis.

Arm/Group Title	Overall
Arm/Group Description	TMZ (Previously Treated) and TMZ (Chemo Naive)
Measure Participants	0

5. Secondary Outcome

Title	Number of Participants Who Experienced Changes in Immunologic Profile (CD4/CD25+ Cells, CD4/Fox-p3+ T Cells) Within a Treatment
Description	Time series plot of the number of circulating cells will be constructed. The resulting plots will be visually inspected for trends within and between treatments. For each cell type, a point and an interval estimate of the number of participants (receiving a given treatment) who had at least a 2-fold increase in the number of circulating cells of that type will be constructed using the properties of the binomial distribution.
Time Frame	up to 2 years

Outcome Measure Data

Analysis Population Description

There is not enough participants to perform this analysis.

Arm/Group Title	Overall
Arm/Group Description	TMZ (Previously Treated) and TMZ (Chemo Naive)
Measure Participants	0

6. Secondary Outcome

Title	Number of Participants Who Experienced Changes in Immunologic Profile (MART-1, Tyrosinase, and gp100) Within a Treatment
Description	For those patients who are HLA-A2+, the maximum post-treatment levels of MART-1, tyrosinase, and gp100 will be determined. For each of these specific melanoma specific antigens, the number of participants (within a given treatment) who gained or maintained immunity based on the maximum post-treatment level of that specific melanoma specific antigen will be determined.
Time Frame	up to 2 years

Outcome Measure Data

Analysis Population Description

There is not enough participants to perform this analysis.

Arm/Group Title	Overall
Arm/Group Description	TMZ (Previously Treated) and TMZ (Chemo Naive)
Measure Participants	0

7. Secondary Outcome

Title	Number of Participants Who Experienced Changes in Immunologic Profile (IFNγ Producing Peptide Specific CTLs) Within a Treatment
Description	For each patient, a time series plot of the number of IFNγ producing peptide specific CTLs will be constructed. The resulting plots will be visually inspected for trends within and between treatments. A point and an interval estimate of the number of participants (receiving a given treatment) who had at least a 2-fold increase in the number of the number of IFNγ producing peptide specific CTLs will be constructed using the properties of the binomial distribution.
Time Frame	up to 2 years

Outcome Measure Data

Analysis Population Description

There is not enough participants to perform this analysis.

Arm/Group Title	Overall
Arm/Group Description	TMZ (Previously Treated) and TMZ (Chemo Naive)
Measure Participants	0

Adverse Events

Arm/Group Title	TMZ (Previously Treated)		TMZ (Chemo Naive)		PC (Previously Treated)		PC (Chemo Naive)
Arm/Group Description	Previously chemotherapy treated cohorts: Temozolomide (TMZ)		Chemotherapy-naive cohorts: Temozolomide (TMZ)		Previously chemotherapy treated cohorts: Paclitaxel and Carboplatin (PC)		Chemotherapy-naive cohorts: Paclitaxel and Carboplatin (PC)
All Cause Mortality
	TMZ (Previously Treated)		TMZ (Chemo Naive)		PC (Previously Treated)		PC (Chemo Naive)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	TMZ (Previously Treated)		TMZ (Chemo Naive)		PC (Previously Treated)		PC (Chemo Naive)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/2 (0%)		1/9 (11.1%)		0/0 (NaN)		0/0 (NaN)
Blood and lymphatic system disorders
Anemia	0/2 (0%)	0	1/9 (11.1%)	1	0/0 (NaN)	0	0/0 (NaN)	0
Other (Not Including Serious) Adverse Events
	TMZ (Previously Treated)		TMZ (Chemo Naive)		PC (Previously Treated)		PC (Chemo Naive)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/2 (50%)		8/9 (88.9%)		0/0 (NaN)		0/0 (NaN)
Blood and lymphatic system disorders
Anemia	1/2 (50%)	1	6/9 (66.7%)	29	0/0 (NaN)	0	0/0 (NaN)	0
General disorders
Fatigue	0/2 (0%)	0	1/9 (11.1%)	1	0/0 (NaN)	0	0/0 (NaN)	0
Infections and infestations
Bronchial infection	0/2 (0%)	0	1/9 (11.1%)	1	0/0 (NaN)	0	0/0 (NaN)	0
Pneumonia	0/2 (0%)	0	1/9 (11.1%)	1	0/0 (NaN)	0	0/0 (NaN)	0
Investigations
Leukopenia	0/2 (0%)	0	3/9 (33.3%)	6	0/0 (NaN)	0	0/0 (NaN)	0
Lymphopenia	0/2 (0%)	0	1/9 (11.1%)	13	0/0 (NaN)	0	0/0 (NaN)	0
Neutropenia	0/2 (0%)	0	2/9 (22.2%)	10	0/0 (NaN)	0	0/0 (NaN)	0
Platelet count decreased	1/2 (50%)	1	4/9 (44.4%)	8	0/0 (NaN)	0	0/0 (NaN)	0
Musculoskeletal and connective tissue disorders
Myalgia	0/2 (0%)	0	1/9 (11.1%)	1	0/0 (NaN)	0	0/0 (NaN)	0

Limitations/Caveats

This trial was stopped prior to achieving its accrual goals due to slow enrollment rate. Early termination leading to small numbers of subjects analyzed.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.