Pilot Study of the Safety/Efficacy of Combination Checkpoint Blockade + External Beam Radiotherapy in Stage IV Melanoma
Condition: Melanoma
MeSH terms: Melanoma
Intervention: Nivolumab; Ipilimumab; Radiotherapy
Intervention description: Nivolumab was administered as an intravenous (IV) infusion over approximately 30 or 90 minutes, with dosing calculated using body weight.; 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.; RT was delivered in accordance with cohort assignment and institutional practices.
Intervention MeSH terms: Nivolumab; Ipilimumab
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Enrollment: 20.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Ipilimumab; Nivolumab; Radiotherapy

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).
    

Eligibility criteria:

        Inclusion Criteria:

          1. 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.

          2. 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).

          3. 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.

          4. 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).

          5. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.

          6. Life expectancy ≥ 4 months.

          7. 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].

          8. Age ≥ 18 years.

          9. Able and willing to give valid written informed consent.

        Exclusion Criteria:

          1. Unresolved immune-related AEs following prior biological therapy. Subjects with
             asymptomatic endocrinopathy may have enrolled.

          2. 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.

          3. History of motor neuropathy considered to be of autoimmune origin (e.g.,
             Guillain-Barre Syndrome, Myasthenia Gravis).

          4. Other active, concurrent malignancy that required ongoing systemic treatment or
             interfered with radiographic assessment of melanoma response as determined by the
             Investigator.

          5. 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.

          6. 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.

          7. History of severe allergic reactions to any unknown allergens or any components of the
             study drugs.

          8. Other serious illnesses (e.g., serious infections requiring antibiotics, bleeding
             disorders).

          9. Requirement of RT to treat brain metastases or receipt of any non-study systemic
             therapy for cancer or any other experimental/investigational treatment.

         10. Mental impairment that may have compromised the ability to give informed consent and
             comply with the requirements of the study.

         11. Lack of availability for immunological and clinical assessments or post-study
             follow-up contact to determine relapse and survival.

         12. 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).

         13. 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.

         14. 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.