Viral Therapy in Treating Patients With Metastatic Melanoma

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00651157
• Collaborator: (none)
• Enrollment: 23
• Location: 1
• Arm: 1
• Duration (Months): 54
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

This phase II trial is studying the side effects and how well viral therapy works in treating patients with metastatic melanoma. Viral therapy may be able to kill tumor cells without damaging normal cells.

Condition or Disease	Intervention/Treatment	Phase
Recurrent Melanoma; Stage IV Melanoma	Biological: wild-type reovirus	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. Assess the antitumor effect of wild-type reovirus (Reolysin®), in terms of tumor response rate and clinical benefit rate (i.e., partial response and complete response), in patients with metastatic melanoma.

2. Assess the toxicity profile of Reolysin® in these patients.

SECONDARY OBJECTIVES:

1. Assess the progression-free survival and overall survival of these patients. II. Assess viral replication in metastatic melanoma deposits after intravenous administration of Reolysin®.

2. Assess the impact of pre-existing anti-reoviral immunity (as represented by p38 expression in pretreatment tumor specimens) on the efficacy and toxicity of Reolysin®.

3. To measure the effect of Reolysin® on the immune system, in terms of dendritic cell activation, T-cell activation, presence of Treg cells in tumor specimens, and the frequency of T cells, B cells, NK cells, and peptide specific cytotoxic T lymphocytes reactive against melanoma differentiation antigen peptides (gp100, MART-1, and tyrosinase).

4. To assess the induction of melanoma specific immune response, in terms of the presence of melanoma differentiation antigens (gp100, MART-1, and tyrosinase) in tumor specimens.

OUTLINE: This is a multicenter study.

Patients receive wild-type reovirus (Reolysin®) IV over 60 minutes on days 1-5. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

Some patients undergo tumor tissue samples collection at baseline and at 1 week after initiation of treatment for correlative laboratory studies. Tissue samples are analyzed for p38/MAPK activation status by IHC; reoviral replication in metastatic deposits by electron microscopy; and immunologic parameters by IHC. Blood samples are collected at baseline and periodically during the study. Blood samples are analyzed for immunologic parameters by tetramer and ELISPOT technology and for neutralizing antibodies against reovirus.

After completion of study treatment, patients are followed every 6 months for 2 years and then annually for up to 5 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 23 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Trial of Intravenous Administration of Reovirus Serotype 3 - Dearing Strain (Reolysin®) in Patients With Metastatic Melanoma
• Study Start Date: Apr 1, 2008
• Actual Primary Completion Date: Dec 1, 2011
• Actual Study Completion Date: Oct 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (viral therapy) Patients receive wild-type reovirus (Reolysin®) IV administered at a dose of 3 x 10^10 TCID50/day in 250 mL 0.9% sodium chloride infused intravenously over 60 minutes daily on days 1-5 of each 28-day cycle. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.	Biological: wild-type reovirus; Given IV: Administered at a dose of 3 x 10^10 TCID50/day in 250 mL 0.9% sodium chloride infused intravenously over 60 minutes daily on days 1-5 of each 28-day cycle.; Other Names: REOLYSIN

Outcome Measures

Primary Outcome Measures

1. Tumor Response [Every 4 weeks after 4 courses of treatment, assessed up to 5 years]

   A tumor response is defined to be a Complete Response (CR) or Partial Response (PR) as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) noted as the objective status on 2 consecutive evaluations at least 4 weeks apart. Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of the largest dimension (LD) of target lesions taking as reference the baseline sum LD.

Secondary Outcome Measures

1. Overall Survival [Time from registration to death due to any cause, assessed up to 5 years]

   Survival time is defined as the time from registration to death due to any cause. The distribution of survival time will be estimated using the method of Kaplan-Meier.

2. Time to Disease Progression [Time from registration to documentation of disease progression, assessed up to 5 years]

   Time to disease progression is defined as the time from registration to documentation of disease progression. If a patient dies without documentation of disease progression, the patient will be considered to have had tumor progression at the time of their death unless there is sufficient documented evidence to conclude no progression occurred prior to death.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Histologically or cytologically confirmed malignant melanoma

• All melanomas, regardless of origin, are allowed

• Metastatic disease

• Measurable disease, defined as ≥ 1 lesion that can be accurately measured in ≥ 1 dimension (longest diameter to be recorded) as ≥ 20mm by conventional techniques or as ≥ 10 mm by spiral CT scan

• Must have ≥ 1 metastatic lesion that can be safely biopsied

• Must have received ≥ 1 prior treatment for metastatic disease

• Not a candidate for curative surgery for metastatic disease

• No known brain metastases

• Eastern Cooperative Oncology Group performance status 0-2

• Life expectancy > 12 weeks

• Total White Blood Cell (WBC) ≥ 3,000/mcL

• Absolute neutrophil count ≥ 1,500/mcL

• Platelet count ≥ 100,000/mcL

• Hemoglobin ≥ 9 g/dL

• Total bilirubin ≤ 1.5 times upper limit of normal (ULN)

• Aspartate Aminotransferase (AST) ≤ 2.5 times ULN

• Creatinine ≤ 1.5 times ULN

• Troponin-T normal

• Left ventricular ejection fraction (LVEF) ≥ 50% by ECHO or MUGA

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception

• Agrees to provide blood and tissue samples for the mandatory translational research component of the study

• Must be able to avoid direct contact with pregnant or nursing women, infants, and immuno compromised individuals during study and for ≥ 3 weeks following the last dose of study agent

• No 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, or myocardial infarction within the past year

• Psychiatric illness/social situation that would preclude study compliance

• No known HIV positivity

• Patients with a clinical history suggestive of an immuno compromised status are required to undergo HIV testing

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

• More than 2 weeks since prior radiotherapy, immunotherapy, or treatment with small molecule cell cycle inhibitors

• No other concurrent investigational agents

• No other concurrent anticancer therapy

Contacts and Locations

Locations

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

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Evanthia Galanis, Mayo Clinic

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00651157
• Other Study ID Numbers: NCI-2009-00233; NCI-2009-00233; MAYO-MC0672; 7848; CDR0000592801; MC0672; 7848; N01CM00070
• First Posted: Apr 2, 2008
• Last Update Posted: Apr 22, 2014
• Last Verified: Feb 1, 2014

• Additional relevant MeSH terms: Melanoma

Study Results

Participant Flow

Recruitment Details	Twenty three participants were enrolled onto this study between August 2008 and January 2010.
Pre-assignment Detail	One participant died prior to receiving any treatment and is not included in this study summary. One participant was found to be ineligible and was not used in the analysis of any endpoint, but was used for reporting toxicity. Therefore, 21 participants were used for the primary analysis and 22 participants are used to report toxicity.

Arm/Group Title	Treatment (Viral Therapy)
Arm/Group Description	Patients receive wild-type reovirus (Reolysin®) IV over 60 minutes on days 1-5. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
Period Title: Overall Study
STARTED	23
COMPLETED	21
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Treatment (Viral Therapy)
Arm/Group Description	Patients receive wild-type reovirus (Reolysin®) IV administered at a dose of 3 x 10^10 TCID50/day in 250 mL 0.9% sodium chloride infused intravenously over 60 minutes daily on days 1-5 of each 28-day cycle. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
Overall Participants	21
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	65
Sex: Female, Male (Count of Participants)
Female	12 57.1%
Male	9 42.9%
Region of Enrollment (participants) [Number]
United States	21 100%

Outcome Measures

1. Primary Outcome

Title	Tumor Response
Description	A tumor response is defined to be a Complete Response (CR) or Partial Response (PR) as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) noted as the objective status on 2 consecutive evaluations at least 4 weeks apart. Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of the largest dimension (LD) of target lesions taking as reference the baseline sum LD.
Time Frame	Every 4 weeks after 4 courses of treatment, assessed up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Viral Therapy)
Arm/Group Description	Patients receive wild-type reovirus (Reolysin®) IV over 60 minutes on days 1-5. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
Measure Participants	21
Complete Response (CR)	0 0%
Partial Response (PR)	0 0%

2. Secondary Outcome

Title	Overall Survival
Description	Survival time is defined as the time from registration to death due to any cause. The distribution of survival time will be estimated using the method of Kaplan-Meier.
Time Frame	Time from registration to death due to any cause, assessed up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Viral Therapy)
Arm/Group Description	Patients receive wild-type reovirus (Reolysin®) IV over 60 minutes on days 1-5. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
Measure Participants	21
Median (95% Confidence Interval) [months]	5.42

3. Secondary Outcome

Title	Time to Disease Progression
Description	Time to disease progression is defined as the time from registration to documentation of disease progression. If a patient dies without documentation of disease progression, the patient will be considered to have had tumor progression at the time of their death unless there is sufficient documented evidence to conclude no progression occurred prior to death.
Time Frame	Time from registration to documentation of disease progression, assessed up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Viral Therapy)
Arm/Group Description	Patients receive wild-type reovirus (Reolysin®) IV over 60 minutes on days 1-5. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
Measure Participants	21
Median (95% Confidence Interval) [days]	45

Adverse Events

Arm/Group Title	Treatment (Viral Therapy)
Arm/Group Description	Patients receive wild-type reovirus (Reolysin®) IV over 60 minutes on days 1-5. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
All Cause Mortality
	Treatment (Viral Therapy)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Treatment (Viral Therapy)
	Affected / at Risk (%)	# Events
Total	11/22 (50%)
Blood and lymphatic system disorders
Hemoglobin decreased	2/22 (9.1%)	2
Cardiac disorders
Atrial fibrillation	1/22 (4.5%)	1
Left ventricular failure	1/22 (4.5%)	1
Gastrointestinal disorders
Dyspepsia	1/22 (4.5%)	1
Dysphagia	1/22 (4.5%)	1
Nausea	1/22 (4.5%)	1
Vomiting	1/22 (4.5%)	1
General disorders
Disease progression	1/22 (4.5%)	1
Fatigue	2/22 (9.1%)	2
Fever	1/22 (4.5%)	1
Investigations
Alkaline phosphatase increased	1/22 (4.5%)	1
Aspartate aminotransferase increased	1/22 (4.5%)	1
Laboratory test abnormal	1/22 (4.5%)	1
Leukocyte count decreased	2/22 (9.1%)	2
Lymphocyte count decreased	1/22 (4.5%)	1
Neutrophil count decreased	2/22 (9.1%)	3
Metabolism and nutrition disorders
Anorexia	1/22 (4.5%)	1
Blood uric acid increased	1/22 (4.5%)	1
Serum albumin decreased	4/22 (18.2%)	5
Serum calcium decreased	2/22 (9.1%)	2
Serum calcium increased	1/22 (4.5%)	1
Serum phosphate decreased	2/22 (9.1%)	2
Serum sodium decreased	1/22 (4.5%)	1
Musculoskeletal and connective tissue disorders
Bone pain	1/22 (4.5%)	1
Muscle weakness	1/22 (4.5%)	1
Nervous system disorders
Depressed level of consciousness	1/22 (4.5%)	1
Ischemia cerebrovascular	1/22 (4.5%)	1
Psychiatric disorders
Confusion	2/22 (9.1%)	2
Insomnia	1/22 (4.5%)	1
Renal and urinary disorders
Ureteric obstruction	1/22 (4.5%)	1
Respiratory, thoracic and mediastinal disorders
Bronchopulmonary hemorrhage	1/22 (4.5%)	1
Cough	1/22 (4.5%)	1
Dyspnea	1/22 (4.5%)	1
Vascular disorders
Hemorrhage	1/22 (4.5%)	1
Other (Not Including Serious) Adverse Events
	Treatment (Viral Therapy)
	Affected / at Risk (%)	# Events
Total	22/22 (100%)
Blood and lymphatic system disorders
Hemoglobin decreased	16/22 (72.7%)	27
Gastrointestinal disorders
Diarrhea	4/22 (18.2%)	6
Nausea	12/22 (54.5%)	16
Vomiting	6/22 (27.3%)	6
General disorders
Chills	11/22 (50%)	16
Fatigue	19/22 (86.4%)	29
Fever	11/22 (50%)	18
Investigations
Leukocyte count decreased	6/22 (27.3%)	9
Lymphocyte count decreased	1/22 (4.5%)	1
Neutrophil count decreased	2/22 (9.1%)	2
Platelet count decreased	9/22 (40.9%)	11
Metabolism and nutrition disorders
Anorexia	12/22 (54.5%)	17
Serum sodium decreased	1/22 (4.5%)	1
Musculoskeletal and connective tissue disorders
Joint pain	1/22 (4.5%)	1
Myalgia	12/22 (54.5%)	14
Nervous system disorders
Headache	3/22 (13.6%)	4
Respiratory, thoracic and mediastinal disorders
Cough	6/22 (27.3%)	11
Dyspnea	5/22 (22.7%)	7
Skin and subcutaneous tissue disorders
Rash desquamating	3/22 (13.6%)	3

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.