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

Not Recruiting

Trial ID: NCT02659540


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).

Official Title

A Pilot (Phase 1) Study to Evaluate the Safety and Efficacy of Combination Checkpoint Blockade (Ipilimumab and Nivolumab) Plus External Beam Radiotherapy in Subjects With Stage IV Melanoma

Stanford Investigator(s)

Sunil Arani Reddy
Sunil Arani Reddy

Clinical Associate Professor, Medicine - Oncology


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

   Clinically significant toxicity or pharmacodynamic effects experienced during any
   prior therapy must have been resolved or stabilized before the first dose of study

   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

   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

   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.


drug: Ipilimumab

drug: Nivolumab

radiation: Radiotherapy

Not Recruiting

Contact Information

Stanford University
School of Medicine
300 Pasteur Drive
Stanford, CA 94305

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