Pilot Study of the Safety/Efficacy of Combination Checkpo... | NCT02659540

Name	Class
Bristol-Myers Squibb	INDUSTRY
Conquer Cancer Foundation	OTHER

Description Module

Detailed Description

All 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, with RT dosing administered to a target lesion as follows:

Cohort A: conventional total palliative dose of 30 Gy delivered over 2 weeks in 10 fractions of 3 Gy each;
Cohort B: hypofractionated high-dose of 27 Gy delivered over 2 weeks in 3 fractions of 9 Gy each.

Eligible subjects were initially enrolled into Cohort A. After 9 evaluable subjects completed at least the first 2 cycles of concurrent ipilimumab and nivolumab treatment, a safety review was performed and determined that the safety of Cohort A was acceptable based on a protocol-specified tolerability threshold of ≤ 7 of 9 subjects experiencing Grade 3 or 4 drug- or radiation-related adverse events (AEs), where Grade 3 or 4 amylase or lipase abnormalities that were not associated with clinical symptoms were not included in the safety assessment. Additional subjects were then accrued to Cohort B.

Subjects were followed on study for 100 days after the last study drug administration. Post-study follow-up, which occurs at least every 12 (± 1) weeks for 3 years after completion of the 100-day on-study follow-up, is still being performed for some patients .

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
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

Name	Type	Description	Arm Group Labels	Other Names
Nivolumab	Drug	Nivolumab was administered as an intravenous (IV) infusion over approximately 30 or 90 minutes, with dosing calculated using body weight.	Cohort A (Conventional RT)

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
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

Measure	Description	Time Frame
Number of Subjects With Tumor Response at Week 12 by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)	Tumor responses were evaluated using appropriate imaging and categorized according to RECIST 1.1 at Screening (up to 28 days before the first dose of study treatment), at Weeks 12, 18, and 24, and every 12 weeks (± 7 days) thereafter until progression or start of alternate anticancer therapy. Per RECIST 1.1, target lesions are categorized as follows: Complete Response (CR): Disappearance of all target lesions; Partial Response (PR): ≥ 30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD): ≥ 20% increase in the sum of the longest diameter of target lesions; Stable Disease (SD): small changes that do not meet above criteria (Eisenhauer et al. Eur J Cancer 2009;45:228-47).

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

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:
1. Symptomatic lymphadenopathy;
2. Bothersome cutaneous disease;
3. Hepatic metastases;
4. 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:
1. White blood cell count ≥ 2000/μL;
2. Absolute neutrophil count ≥ 1500/μL;
3. Platelets ≥ 100,000/μL;
4. Hemoglobin ≥ 9 g/dL;
5. Aspartate aminotransferase and alanine aminotransferase ≤ 3 × upper limit of normal (ULN);
6. Total bilirubin ≤ 1.5 × ULN (< 3 mg/dL for subjects with Gilbert's disease);
7. Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 40 mL/min (if using the Cockcroft-Gault formula below):
  - Female CrCl = [(140 - age in years) x weight in kg x 0.85] / [72 x serum creatinine in mg/dL];
  - Male CrCl = [(140 - age in years) x weight in kg x 1.00] / [72 x serum creatinine in mg/dL].
Age ≥ 18 years.
Able and willing to give valid written informed consent.

Exclusion Criteria:

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.

Name	Affiliation	Role
Michael Postow, MD	Memorial Sloan Kettering Cancer Center	Study Chair

Facility	Status	City	State	ZIP	Country	Contacts
Stanford Cancer Institute		Stanford	California	94304	United States
Memorial Sloan Kettering Cancer Center

PubMed Identifier	Type	Citation	Retractions
19097774	Background	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.
	Background	Bohnsack O, Hoos A, Ludajic K. Adaptation of the immune related response criteria: irRECIST. Ann Oncol. 2014;25(Supplement 4):iv361-iv72.

ID	Title	Description
FG000	Cohort A (Conventional RT)	Subjects received concurrent ipilimumab (3 mg/kg IV) and nivolumab (1 mg/kg IV) 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 IV every 2 weeks through Week 18. Continued nivolumab monotherapy was permitted beyond Week 18 at the Investigator's discretion as either 240 mg IV every 2 weeks or 480 mg IV 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.
FG001	Cohort B (Hypofractionated RT)	Subjects received concurrent ipilimumab (3 mg/kg IV) and nivolumab (1 mg/kg IV) 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 IV every 2 weeks through Week 18. Continued nivolumab monotherapy was permitted beyond Week 18 at the Investigator's discretion as either 240 mg IV every 2 weeks or 480 mg IV 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.

ID	Title	Description
BG000	Cohort A (Conventional RT)	Subjects received concurrent ipilimumab (3 mg/kg IV) and nivolumab (1 mg/kg IV) 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 IV every 2 weeks through Week 18. Continued nivolumab monotherapy was permitted beyond Week 18 at the Investigator's discretion as either 240 mg IV every 2 weeks or 480 mg IV 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.

Units	Counts
Participants	BG000

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Continuous			Median

Outcome Measures Module

Outcome Measures

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

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.

The population comprises all subjects who received at least one dose of study treatment.

Posted

Count of Participants

Participants

Up to 25 months

ID	Title	Description
OG000	Cohort A (Conventional RT)	Subjects received concurrent ipilimumab (3 mg/kg IV) and nivolumab (1 mg/kg IV) 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 IV every 2 weeks through Week 18. Continued nivolumab monotherapy was permitted beyond Week 18 at the Investigator's discretion as either 240 mg IV every 2 weeks or 480 mg IV 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.

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Cohort A (Conventional RT)	Subjects received concurrent ipilimumab (3 mg/kg IV) and nivolumab (1 mg/kg IV) 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 IV every 2 weeks through Week 18. Continued nivolumab monotherapy was permitted beyond Week 18 at the Investigator's discretion as either 240 mg IV every 2 weeks or 480 mg IV 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.

ID	Term
D018358	Neuroendocrine Tumors
D017599	Neuroectodermal Tumors
D009373	Neoplasms, Germ Cell and Embryonal
D009370	Neoplasms by Histologic Type

ID	Term
D061067	Antibodies, Monoclonal, Humanized
D000911	Antibodies, Monoclonal
D000906	Antibodies
D007136	Immunoglobulins