Pembrolizumab, Standard Chemotherapy, Tumor Infiltrating Lymphocytes, and High- or Low-Dose Aldesleukin in Treating Patients With Metastatic Melanoma

NCT02500576 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: 2014-0922NCI-2015-01395
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

Brief Summary

This randomized phase II trial studies how well giving pembrolizumab with standard chemotherapy, tumor infiltrating lymphocytes (TIL), and aldesleukin works in treating patients with melanoma that has spread to other areas of the body. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as cyclophosphamide and fludarabine phosphate, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving an infusion of TIL, or white blood cells, may help stimulate the immune system to help kill more cells. Aldesleukin may also stimulate the white blood cells to kill melanoma cells. Giving pembrolizumab together with standard chemotherapy, TIL, and high- or low-dose aldesleukin may help stop the melanoma from spreading.

Conditions

Metastatic Melanoma; Stage IIIB Cutaneous Melanoma AJCC v7; Stage IIIC Cutaneous Melanoma AJCC v7; Stage IV Cutaneous Melanoma AJCC v6 and v7

Outcome Measures

Primary Outcomes (1)

• Overall Response Rate in Each Arm

  The overall response rate will be computed separately by arm and presented with exact 95% confidence intervals. The overall response rate will be compared between the two treatment arms by using Fisher's exact test. The association between overall response rate and the same covariates will be assessed by using logistic regression.

  Up to 5 years

Secondary Outcomes (3)

• Overall Survival

  Up to 5 years

• Progression-free Survival

  Up to 5 years

• Change in Blood and Tumor Biomarkers

  Baseline and weeks 3, 6, and 9

Study Arms (2)

Arm I (pembrolizumab, high-dose aldesleukin)

EXPERIMENTAL

Patients receive standard lymphodepleting chemotherapy comprising cyclophosphamide IV over 2 hours on days -7 and -6 followed by fludarabine phosphate IVPB over 15-30 minutes on days -5 to -1. Patients also receive therapeutic tumor infiltrating lymphocytes IV over 15-60 minutes on day 0 followed by high-dose aldesleukin IV over 15 minutes every 8-16 hours for up to 15 doses on days 1-5. Beginning between 21-28 days after TIL infusion, patients receive maintenance therapy comprising pembrolizumab IV over 30 minutes every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

Biological: Aldesleukin; Drug: Cyclophosphamide; Drug: Fludarabine Phosphate; Other: Laboratory Biomarker Analysis; Biological: Pembrolizumab; Other: Quality-of-Life Assessment; Biological: Therapeutic Tumor Infiltrating Lymphocytes

Arm II (pembrolizumab, low-dose aldesleukin)

EXPERIMENTAL

Patients receive standard lymphodepleting chemotherapy comprising cyclophosphamide and fludarabine phosphate and therapeutic tumor infiltrating lymphocytes as in Arm I, followed approximately 6 hours later by low-dose aldesleukin SC for 14 days. Patients also receive pembrolizumab as in Arm I.

Biological: Aldesleukin; Drug: Cyclophosphamide; Drug: Fludarabine Phosphate; Other: Laboratory Biomarker Analysis; Biological: Pembrolizumab; Other: Quality-of-Life Assessment; Biological: Therapeutic Tumor Infiltrating Lymphocytes

Interventions

Aldesleukin BIOLOGICAL

Given IV or SC

Also known as: 125-L-Serine-2-133-interleukin 2, Proleukin, r-serHuIL-2, Recombinant Human IL-2, Recombinant Human Interleukin-2

Arm I (pembrolizumab, high-dose aldesleukin); Arm II (pembrolizumab, low-dose aldesleukin)

Cyclophosphamide DRUG

Given IV

Also known as: (-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719

Arm I (pembrolizumab, high-dose aldesleukin); Arm II (pembrolizumab, low-dose aldesleukin)

Fludarabine Phosphate DRUG

Given IVPB

Also known as: 2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, SH T 586

Arm I (pembrolizumab, high-dose aldesleukin); Arm II (pembrolizumab, low-dose aldesleukin)

Laboratory Biomarker Analysis OTHER

Correlative studies

Arm I (pembrolizumab, high-dose aldesleukin); Arm II (pembrolizumab, low-dose aldesleukin)

Pembrolizumab BIOLOGICAL

Given IV

Also known as: Keytruda, Lambrolizumab, MK-3475, SCH 900475

Arm I (pembrolizumab, high-dose aldesleukin); Arm II (pembrolizumab, low-dose aldesleukin)

Quality-of-Life Assessment OTHER

Ancillary studies

Also known as: Quality of Life Assessment

Arm I (pembrolizumab, high-dose aldesleukin); Arm II (pembrolizumab, low-dose aldesleukin)

Therapeutic Tumor Infiltrating Lymphocytes BIOLOGICAL

Given IV

Also known as: Tumor Infiltrating Lymphocytes

Arm I (pembrolizumab, high-dose aldesleukin); Arm II (pembrolizumab, low-dose aldesleukin)

Eligibility Criteria

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

You may qualify if:

• TURNSTILE I - SCREENING:
• Patients must have metastatic melanoma or stage III in-transit, subcutaneous, or regional nodal disease
• Patients must have a lesion amenable to resection for the generation of TIL on MD Anderson protocol 2004-0069
• Patients must receive a magnetic resonance imaging (MRI)/computed tomography (CT)/positron emission tomography (PET) of the brain within 6 months of signing informed consent; if new central nervous system (CNS) lesions are present, patient must have definitive treatment (including surgery or radiation); principal investigator (PI) or his designee should make final determination regarding enrollment
• Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 - 1 within 30 days of signing informed consent
• Patients previously treated with immunotherapy, targeted therapy, or no therapy (treatment naive) will be eligible
• Patients receiving cytotoxic agents will be evaluated by the PI or his designee for eligibility suitability
• Patients with a negative pregnancy test (urine or serum) must be documented within 14 days of screening for women of childbearing potential (WOCBP); a WOCBP has not undergone a hysterectomy or who has not been naturally postmenopausal for at least 12 consecutive months (i.e. who has not had menses at any time in the preceding 12 consecutive months)
• TURNSTILE II - TREATMENT:
• Patients must sign the treatment consent document before Turnstile II screening procedures; before the treatment starts and at each visit, the patient will be asked to complete two quality of life questionnaires; It should take about 15 minutes to complete the questionnaires (Functional Assessment of Cancer Therapy General \[FACT-G\], FACT-Melanoma); patients must fulfill all of the following criteria to be eligible for Turnstile II of the study
• Patients must have adequate TIL that were previously harvested and then cryopreserved on MD Anderson Cancer Center (MDACC) protocol 2004-0069
• Patients who have had prior therapy (BRAF inhibitors, ipilimumab, anti PD-1 antibody or anti PD-L1 antibody) or treatment naive patients are eligible as long as toxicity from therapy is grade =\< 1 or at baseline
• Patients must have at least one biopsiable measurable metastatic melanoma, lesion \> 1 cm and must be amenable to undergoing serial biopsies through the course of therapy; this lesion must not be documented as one of the target lesions
• Patients may have central nervous system (CNS) metastases which have been treated and are radiographically stable for at least 4 weeks
• Patients of both genders must practice birth control for four months after receiving the preparative regimen (lymphodepletion) and continue to practice birth control throughout the study; patients must have a documented negative pregnancy test (urine or serum) for women who have menstruated in the past 12 months and without sterilization surgery

You may not qualify if:

• TURNSTILE I - SCREENING
• Active systemic infections requiring intravenous antibiotics, coagulation disorders or other major medical illnesses of the cardiovascular, respiratory or immune system; PI or his designee shall make the final determination regarding appropriateness of enrollment
• Primary immunodeficiency and need for chronic steroid therapy, exception: patients on chronic physiological dose of steroid equivalent to prednisone \< 10 mg/day is allowed
• Patients who are pregnant or nursing
• Presence of a significant psychiatric disease, which in the opinion of the principal investigator or his designee, would prevent adequate informed consent
• TURNSTILE II - TREATMENT
• Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to initiation of lymphodepletion; exception: patients on chronic physiologic dose of steroid equivalent to prednisone \< 10 mg/day is allowed
• Has not recovered (i.e., =\< grade 1 or at baseline) from adverse events due to investigational or standard agents administered more than 4 weeks earlier
• Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to lymphodepletion or who has not recovered (i.e., =\< grade 1 or at baseline) from adverse events due to a previously administered agent
• Note: subjects with =\< grade 2 neuropathy, alopecia, hypophysitis stable on physiologic dose of steroid equivalent to prednisone \< 10 mg/day, hypothyroidism stable on hormone replacement are an exception to this criterion and may qualify for the study
• Note: if subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
• Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to initiation of lymphodepletion
• Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease; subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule; subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study; subjects with hypothyroidism stable on hormone replacement or Sjogren's syndrome will not be excluded from the study; subjects with hypophysitis stable on physiologic dose of steroid will not be excluded from the study

Sponsors & Collaborators

• M.D. Anderson Cancer Center: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

M D Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Links

• University of Texas MD Anderson Cancer Center Website

MeSH Terms

Conditions

Melanoma

Interventions

aldesleukin; Cyclophosphamide; fludarabine phosphate; pembrolizumab

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

Results Point of Contact

• Title: Dr. Rodabe Amaria
• Organization: M D Anderson Cancer Center

rnamaria@mdanderson.org

(713) 792-2921

Study Officials

• Rodabe N Amaria

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 14, 2015
• First Posted: July 16, 2015
• Study Start: August 7, 2015
• Primary Completion: October 12, 2022
• Study Completion: October 12, 2022
• Last Updated: January 15, 2025
• Results First Posted: January 15, 2025

Record last verified: 2025-01

Locations

US (1)