CTLA-4 Blockade and Low Dose Cyclophosphamide in Patients With Advanced Malignant Melanoma

NCT01740401 | Terminated Phase 2 Results DMC

• 2 other identifiers: GCO 14-0677114660
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to see whether the combination of low-dose Cyclophosphamide and Anti-CTLA4 (Ipilimumab) will stop tumor growth in patients with advanced skin cancer. The investigators expect to see an increase in response rate of the combination over Anti-CTLA-4 alone and estimate a response rate of approximately 20 % in the proposed population.

Conditions

Melanoma

Keywords

Melanoma; Advanced Malignant Melanoma; Anti CTLA4 Blockade; Progression Free Survival; Interventional Therapy; Phase II Clinical Trial; Immunotherapy; T Cell Activation

Outcome Measures

Primary Outcomes (1)

• The Anti-tumor Activity of the Combination of Low Dose Cyclophosphamide and CTLA-4 Blockade Using Objective Response Rate (ORR)

  Objective response rate (ORR) using mWHO RC. 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.

  12 weeks

Secondary Outcomes (2)

• Progression-free Survival

  Week 60

• T Regulatory Cell Profile in Peripheral Blood

  Week 60

Other Outcomes (1)

• Tumor-specific T Cell Responses Will be Measured in a Subset of Patients Who Have Biopsy Accessible Tumor and Have Tumor Biopsies Taken.

  Week 48

Study Arms (1)

Cyclophosphamide, Ipilimumab

EXPERIMENTAL

Treatment: Cyclophosphamide 300 mg/m2 po - Day 1 of Weeks 1, 4, 7, and 10, for a total of 4 doses; (premedication prior to each dose of Cyclophosphamide 8mg Zofran po, then prn) Ipilimumab 10 mg/kg iv - Day 3 of Weeks 1, 4, 7, and 10 for a total of 4 doses Maintenance treatment will be given on Weeks 24, 36, and 48 Ipilimumab 10 mg/kg iv

Drug: Cyclophosphamide

Interventions

Cyclophosphamide DRUG

This study consists of a Treatment Period, D1 Zofran 8mg pre-Cyclophosphamide 300mg/mg2 po and D3 Ipilimumab 10mg/kg iv wks 1,4,7 and 10; Tumor assessment at week 12; Follow-Up period weeks 13,16,and 20 with no treatment; Maintenance Period, D1 10mg/kg iv wks 24,36,48 and 60. Week 40=end of treatment; week 60=end of study

Also known as: Ipilimumab (BMS-734016, MDX010, MDX-CTLA4), Cytoxin

Cyclophosphamide, Ipilimumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Men \& women, ages ≥18
• Willing/able to give written informed consent.
• Histologic diagnosis of unresectable AJCC Stage III/IV malignant melanoma
• At least 2wks must have elapsed since last chemotherapy, immunotherapy, hormonal therapy, radiotherapy or major surgery \& beginning of protocol therapy. At least 6wks for nitrosoureas, mitomycin C, \& liposomal doxorubicin
• Toxicity related to prior therapy must either have returned to ≤ grade 1 or baseline.
• Two punch tumor biopsy at Screening and Wk12 (4mm diameter) must be provided for immune analysis/staining if patients have accessible disease. Biopsies are optional during the Maintenance Period.Site of tumor biopsy s/n be only site of measurable disease. Minimum of 5 out of 1st 10 patients in stage I of the protocol must have biopsy accessible disease.
• Patients must have measurable disease defined as @ least 1 lesion that can be accurately measured in @ least 1 dimension (longest diameter to be recorded) as \>20 mm with conventional techniques or as \>10 mm with spiral CT scan.
• Required values for initial laboratory tests:
• WBC ≥ 2000/uL
• ANC ≥ 1000/uL
• Platelets ≥ 50 x 103/uL
• Hemoglobin ≥ 9.5 g/dL
• Creatinine ≤ 3.0 x ULN
• AST/ALT ≤ 2.5 x ULN for patients without liver metastasis, ≤ 5 x ULN for patients with liver metastasis
• Bilirubin ≤ 3.0 x ULN, (except patients with Gilbert's Syndrome, who must have a total bilirubin less than 3.0 mg/dL)

You may not qualify if:

• Any other malignancy from which patient has been disease-free for less than 5yrs, with the exception of adequately treated \& cured basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the cervix.
• Autoimmune disease: Patients with a history of inflammatory bowel disease, including ulcerative colitis and Crohn's Disease, are excluded from this study, as are patients with a history of symptomatic disease (eg rheumatoid arthritis, systemic progressive sclerosis \[scleroderma\], systemic lupus erythematosus, autoimmune vasculitis \[eg Wegener's Granulomatosis\]); motor neuropathy considered of autoimmune origin (eg Guillain-Barre Syndrome and Myasthenia Gravis).
• Any underlying medical or psychiatric condition, which in the opinion of investigator will make administration of ipilimumab hazardous or obscure interpretation of AEs, like a condition associated with frequent diarrhea.
• Uncontrolled or significant cardiovascular disease
• Any non-oncology vaccine therapy used for prevention of infectious diseases (for up to 1mo before/after any dose of ipilimumab).
• History of prior treatment with ipilimumab or prior CD137 agonist or CTLA 4 inhibitor or agonist.
• Concomitant therapy with any of following: IL 2, interferon, other non-study immunotherapy regimens; immunosuppressive agents; other investigation therapies; or chronic use of systemic corticosteroids (\>60mg prednisone/day).
• Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (eg infectious) illness.
• Women of childbearing potential (WOCBP), defined above who:
• are unwilling/unable to use an acceptable method of contraception to avoid pregnancy for their entire study period and for at least 26wks after cessation of study drug, or
• have a positive pregnancy test at baseline, or
• are pregnant or breastfeeding.
• Persons of reproductive potential who are unwilling to use an adequate method of contraception throughout treatment \& for at least 26wks after ipilimumab is stopped.

Sponsors & Collaborators

• Icahn School of Medicine at Mount Sinai: lead
• Bristol-Myers Squibb: collaborator

Study Sites (1)

New York University Langone Clinical Cancer Center

New York, New York, 10016, United States

Location

MeSH Terms

Conditions

Melanoma

Interventions

Cyclophosphamide; Ipilimumab; CTLA-4 Antigen

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Immune Checkpoint Proteins; Costimulatory and Inhibitory T-Cell Receptors; Receptors, Immunologic; Receptors, Cell Surface; Membrane Proteins; Antigens, Differentiation, T-Lymphocyte; Antigens, Differentiation; Antigens, Surface; Antigens; Biological Factors; Biomarkers

Results Point of Contact

• Title: Dr. Nina Bhardwaj
• Organization: Icahn School of Medicine at Mount Sinai

nina.bhardwaj@mssm.edu

212-824-8427

Study Officials

• Nina Bhardwaj, MD,PhD

  NYU Langone Health

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director, Tumor Vaccine Program

Study Record Dates

• First Submitted: November 29, 2012
• First Posted: December 4, 2012
• Study Start: October 1, 2012
• Primary Completion: December 1, 2013
• Study Completion: December 1, 2014
• Last Updated: December 6, 2017
• Results First Posted: April 26, 2017

Record last verified: 2017-10

Locations

US (1)