Pilot Study of the Safety/Efficacy of Combination Checkpoint Blockade + External Beam Radiotherapy in Stage IV Melanoma

NCT02659540 | Completed Phase 1 Results FDA Drug

• 1 other identifier: LUD2015-006
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 2

Brief Summary

This is an ongoing, Phase 1, open-label, multicenter, pilot study of the checkpoint antibodies ipilimumab and nivolumab in combination with radiotherapy (RT) in 18 subjects with unresectable Stage IV melanoma. The primary study objective is to evaluate the safety of study treatment. Secondary objectives are to evaluate objective response rate (ORR) and disease control rate (DCR) at Weeks 12 and 18, duration of response, progression-free survival (PFS), and overall survival (OS).

Conditions

Melanoma

Keywords

Ipilimumab; Nivolumab; Radiotherapy

Outcome Measures

Primary Outcomes (1)

• Number of Subjects With Treatment-emergent Adverse Events (TEAEs)

  Toxicity was graded in accordance with the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.03. Adverse events (AEs) were reported based on clinical laboratory tests, vital signs, physical examinations, and any other medically indicated assessments, including subject interviews, from the time informed consent was signed through 100 days after the last dose of study treatment. Treatment-emergent AEs were those that occurred or worsened after administration of the first dose of study treatment.

  Up to 25 months

Secondary Outcomes (7)

• Number of Subjects With Tumor Response at Week 12 by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)

  12 weeks

• Number of Subjects With Tumor Response at Week 18 by RECIST 1.1

  18 weeks

• Number of Subjects With Tumor Response at Week 12 by Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST)

  12 weeks

• Number of Subjects With Tumor Response at Week 18 by irRECIST

  18 weeks

• Duration of Response

  Up to 3 years post-study

Study Arms (2)

Cohort A (Conventional RT)

EXPERIMENTAL

Subjects received concurrent ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) every 3 weeks for 4 doses (i.e., Weeks 1, 4, 7 and 10), followed by nivolumab monotherapy administered at a dose of 240 mg every 2 weeks through Week 18. Continued nivolumab monotherapy was permitted beyond Week 18 at the Investigator's discretion as either 240 mg every 2 weeks or 480 mg every 4 weeks starting at Week 20. Extracranial RT was initiated after the first dose and before the second dose of immunotherapy and was administered to a target lesion at a conventional total palliative dose of 30 Gy delivered over 2 weeks in 10 fractions of 3 Gy each.

Drug: Nivolumab; Drug: Ipilimumab; Radiation: Radiotherapy

Cohort B (Hypofractionated RT)

EXPERIMENTAL

Subjects received concurrent ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) every 3 weeks for 4 doses (i.e., Weeks 1, 4, 7 and 10), followed by nivolumab monotherapy administered at a dose of 240 mg every 2 weeks through Week 18. Continued nivolumab monotherapy was permitted beyond Week 18 at the Investigator's discretion as either 240 mg every 2 weeks or 480 mg every 4 weeks starting at Week 20. Extracranial RT was initiated after the first dose and before the second dose of immunotherapy and was administered to a target lesion at a hypofractionated high-dose of 27 Gy delivered over 2 weeks in 3 fractions of 9 Gy each.

Drug: Nivolumab; Drug: Ipilimumab; Radiation: Radiotherapy

Interventions

Nivolumab DRUG

Nivolumab was administered as an intravenous (IV) infusion over approximately 30 or 90 minutes, with dosing calculated using body weight.

Also known as: Opdivo

Cohort A (Conventional RT); Cohort B (Hypofractionated RT)

Ipilimumab DRUG

Ipilimumab was administered as an IV infusion over approximately 30 or 90 minutes, with dosing calculated using body weight. The ipilimumab infusion was initiated approximately 30 minutes after the end of the nivolumab infusion on applicable dosing days.

Also known as: Yervoy

Cohort A (Conventional RT); Cohort B (Hypofractionated RT)

Radiotherapy RADIATION

RT was delivered in accordance with cohort assignment and institutional practices.

Cohort A (Conventional RT); Cohort B (Hypofractionated RT)

Eligibility Criteria

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

You may qualify if:

• Histologic diagnosis of Stage IV metastatic melanoma, with 1 melanoma lesion that could be safely irradiated and, in the opinion of the radiation oncologist, was of benefit to the subject to irradiate (note: subjects with primary ocular and mucosal melanoma were permitted). Lesions may have included, but were not limited to:
• Symptomatic lymphadenopathy;
• Bothersome cutaneous disease;
• Hepatic metastases;
• Pulmonary metastases.
• Excluding the lesion intended to undergo radiation, subjects must have had at least 1 unresectable, non-bony lesion that was measurable radiographically (based on Response Evaluation Criteria in Solid Tumors \[RECIST\] 1.1).
• Any number of prior therapies (including none). For subjects who had received prior systemic treatment with cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), programmed cell death-1 (PD-1), and/or programmed cell death ligand-1 (PD-L1) therapy, the last monoclonal antibody administration should have been no less than 4 weeks prior to start of this protocol therapy and all prior side effects must have resolved to grade 1 or less by the time of the start of this protocol therapy.
• Subjects must have:
• Completed investigational therapy, other immunotherapy, or prior RT at least 28 days before administration of the first dose of study drug(s)
• Completed chemotherapy or targeted therapy at least 14 days before administration of the first dose of study drug(s)
• Sufficiently recovered from prior surgery as determined by the treating Investigator.
• Clinically significant toxicity or pharmacodynamic effects experienced during any prior therapy must have been resolved or stabilized before the first dose of study drug(s).
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
• Life expectancy ≥ 4 months.
• Screening laboratory parameters:

You may not qualify if:

• Unresolved immune-related AEs following prior biological therapy. Subjects with asymptomatic endocrinopathy may have enrolled.
• Active autoimmune disease or any condition requiring systemic treatment with either corticosteroids (\>10 mg daily of prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses \> 10 mg daily prednisone equivalents were permitted in the absence of active autoimmune disease.
• History of motor neuropathy considered to be of autoimmune origin (e.g., Guillain-Barre Syndrome, Myasthenia Gravis).
• Other active, concurrent malignancy that required ongoing systemic treatment or interfered with radiographic assessment of melanoma response as determined by the Investigator.
• Active brain metastases or leptomeningeal metastases. Subjects with brain metastases were eligible if metastases had been treated and there was no magnetic resonance imaging (MRI) evidence of progression for 4 weeks or more after treatment was completed and within 28 days prior to the first dose of nivolumab administration. There must also have been no requirement for immunosuppressive doses of systemic corticosteroids (\> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration.
• Known immunodeficiency or human immunodeficiency virus, Hepatitis B, or Hepatitis C positivity. Antibody to Hepatitis B or C without evidence of active infection may have been allowed.
• History of severe allergic reactions to any unknown allergens or any components of the study drugs.
• Other serious illnesses (e.g., serious infections requiring antibiotics, bleeding disorders).
• Requirement of RT to treat brain metastases or receipt of any non-study systemic therapy for cancer or any other experimental/investigational treatment.
• Mental impairment that may have compromised the ability to give informed consent and comply with the requirements of the study.
• Lack of availability for immunological and clinical assessments or post-study follow-up contact to determine relapse and survival.
• Women who were breastfeeding or who were pregnant as evidenced by a positive serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin) performed within 14 days of the first dose of study drug and by a urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin) within 24 hours of the first dose of study drug(s).
• Females of childbearing potential who were sexually active with a nonsterilized male partner must have used 2 methods of effective contraception from screening, and must have agreed to continue using such precautions for 23 weeks after the final dose of investigational product; cessation of birth control after this point should have been discussed with a responsible physician. Periodic abstinence, the rhythm method, and the withdrawal method were not acceptable methods of birth control.
• \[Females of childbearing potential were defined as those who were not surgically sterile (i.e., bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or postmenopausal (defined as 12 months with no menses without an alternative medical cause).\] Nonsterilized males who were sexually active with a female partner of childbearing potential must have used 2 acceptable methods of effective contraception from Day 1 and for 31 weeks after receipt of the final dose of investigational product.
• Any condition that, in the clinical judgment of the treating physician, was likely to interfere with the interpretability of the data or prevent the subject from complying with any aspect of the protocol or that may have put the subject at unacceptable risk.

Sponsors & Collaborators

• Ludwig Institute for Cancer Research: lead
• Bristol-Myers Squibb: collaborator
• Conquer Cancer Foundation: collaborator

Study Sites (2)

Stanford Cancer Institute

Stanford, California, 94304, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Related Publications (2)

• Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. doi: 10.1016/j.ejca.2008.10.026.

  PMID: 19097774 BACKGROUND

• Bohnsack O, Hoos A, Ludajic K. Adaptation of the immune related response criteria: irRECIST. Ann Oncol. 2014;25(Supplement 4):iv361-iv72.

  BACKGROUND

MeSH Terms

Conditions

Melanoma

Interventions

Nivolumab; Ipilimumab; Radiotherapy

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)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Therapeutics

Results Point of Contact

• Title: Jonathan Skipper PhD
• Organization: Ludwig Institute for Cancer Research

jskipper@lcr.org

(212) 450-1539

Study Officials

• Michael Postow, MD

  Memorial Sloan Kettering Cancer Center

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 6, 2016
• First Posted: January 20, 2016
• Study Start: October 13, 2016
• Primary Completion: May 9, 2019
• Study Completion: July 27, 2020
• Last Updated: October 28, 2022
• Results First Posted: January 2, 2020

Record last verified: 2022-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)