Clinical Trials /

Safety of SBRT With Anti-PD1 and Anti-IL-8 for the Treatment of Multiple Metastases in Advanced Solid Tumors

NCT04572451

Description:

Nivolumab (and other agents affecting the anti-programmed death-1 [anti-PD-1] pathway) have demonstrated anti-tumor activity in multiple tumor types including non-small cell lung cancer (NSCLC), melanoma (MEL), renal cell carcinoma (RCC), and other cancers. However, there remains a large proportion of participants who do not achieve durable clinical benefit to nivolumab monotherapy. Combinations of immune-oncology (IO) agents with complimentary mechanisms as well as radiation represent a promising strategy to improve response rates to immunotherapy. In this phase I study, radiation will be used in combination with IO agents nivolumab and anti-IL-8 (BMS-986253) to assess toxicity by organ system. The study will determine the safe doses of radiation by organ site in conjunction with nivolumab and BMS-986253. The study will also provide the opportunity to evaluate changes in the tumor microenvironment induced by the treatment.

Related Conditions:
  • Malignant Solid Tumor
  • Melanoma
  • Renal Cell Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Safety of SBRT With Anti-PD1 and Anti-IL-8 for the Treatment of Multiple Metastases in Advanced Solid Tumors
  • Official Title: Phase I Study Investigating the Safety of Stereotactic Body Radiotherapy (SBRT) With Anti-PD1 and Anti-IL-8 for the Treatment of Multiple Metastases in Advanced Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: HCC 20-228
  • NCT ID: NCT04572451

Conditions

  • Melanoma
  • Carcinoma, Renal Cell
  • Unresectable Solid Tumors

Interventions

DrugSynonymsArms
nivolumabOpdivo®, Anti-PD-1Nivolumab (Anti-PD-1) + BMS-986253 (Anti-IL-8) + SBRT
BMS-986253Anti-IL-8Nivolumab (Anti-PD-1) + BMS-986253 (Anti-IL-8) + SBRT

Purpose

Nivolumab (and other agents affecting the anti-programmed death-1 [anti-PD-1] pathway) have demonstrated anti-tumor activity in multiple tumor types including non-small cell lung cancer (NSCLC), melanoma (MEL), renal cell carcinoma (RCC), and other cancers. However, there remains a large proportion of participants who do not achieve durable clinical benefit to nivolumab monotherapy. Combinations of immune-oncology (IO) agents with complimentary mechanisms as well as radiation represent a promising strategy to improve response rates to immunotherapy. In this phase I study, radiation will be used in combination with IO agents nivolumab and anti-IL-8 (BMS-986253) to assess toxicity by organ system. The study will determine the safe doses of radiation by organ site in conjunction with nivolumab and BMS-986253. The study will also provide the opportunity to evaluate changes in the tumor microenvironment induced by the treatment.

Detailed Description

      This is a study of SBRT in combination with nivolumab and BMS-986253, a monoclonal antibody
      (mAb) against human interleukin-8 (IL-8), conducted in humans with advanced solid tumors.
      This study will evaluate the safety profile, tolerability and preliminary efficacy of SBRT in
      combination with BMS-986253 and nivolumab in participants with advanced solid tumors and
      detectable levels of IL-8 in the serum. The study will be conducted in 2 parts.

      Part 1 will evaluate the safety, tolerability of different doses of SBRT in combination with
      nivolumab (480 mg) and BMS-986253 (2400mg) every 2 weeks (Q2W) in participants with advanced
      solid tumors and detectable levels of IL-8 in the serum. This phase will begin with a cohort
      of participants who will receive a 2,400 mg flat dose of BMS-986253 Q2W combined with 480 mg
      flat dose of nivolumab Q4W along with SBRT (the dose is dependent on the irradiating organ).

      Part 2 will assess preliminary efficacy of SBRT in combination with nivolumab and BMS-986253
      in participants with advanced/metastatic/unresectable melanoma and RCC who progressed on
      anti-PD-(L)1 therapy and have detectable levels of IL-8 in the serum.

      This study aims to determine that safe doses will be found using ablative doses of SBRT with
      concurrent IO agents. Additional safety, tolerability and preliminary efficacy information in
      specific patient population will be gathered. Twenty participants with anti-PD-(L)1
      refractory advanced/unresectable/metastatic melanoma and RCC and with serum IL-8 above the
      lower limit of quantitation (LLOQ) will be enrolled into efficacy phase.

      This proposal is intended to incorporate SBRT as a direct therapeutic which is in contrast
      with other proposals evaluating response at distant sites after isolated metastasis
      radiation. With this intent, the results of this study will be directly applicable to
      potential expansion cohorts and ongoing clinical need.
    

Trial Arms

NameTypeDescriptionInterventions
Nivolumab (Anti-PD-1) + BMS-986253 (Anti-IL-8) + SBRTExperimental480 mg intravenous nivolumab (BMS-936558-01) every 4 weeks + 2,400 mg intravenous BMS-986253 (Anti-IL-8) every 2 weeks + Stereotactic Body Radiotherapy (SBRT)
  • nivolumab
  • BMS-986253

Eligibility Criteria

        Inclusion Criteria:

          -  SAFETY COHORT

               1. Patients with advanced/metastatic/unresectable solid tumors progressed on
                  standard therapies. Patients with melanoma and RCC will make up approximately 30%
                  of total cohort.

               2. Patients with 1-4 tumor sites that can be irradiated safely

               3. Patients who have detectable serum IL-8 (> 10 pg/mL) at baseline

               4. Age > or equal 18 years

               5. ECOG performance status 0 or 1

               6. Patients must have normal organ and marrow function as defined below:

                    -  Leukocytes ≥ 3000/mcL;

                    -  absolute neutrophil count ≥ 1500/mcL;

                    -  Platelets ≥ 100,000/mcL;

                    -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 ×
                       upper limit of normal (ULN) ;

                    -  Total bilirubin ≤ 1.5 × ULN (except participants with Gilbert's Syndrome who
                       must have normal direct bilirubin)

                    -  Serum creatinine ≤ 1.5 × ULN Patients must have measurable disease, defined
                       as at least one lesion that can be accurately measured in at least one
                       dimension (longest diameter to be recorded for non- nodal lesions and short
                       axis for nodal lesions) as ≥10 mm (≥1 cm) with CT scan, MRI, or calipers by
                       clinical exam

               7. Ability to understand and the willingness to sign a written informed consent
                  document.

               8. Reproductive status

                    -  Women of childbearing potential (WOCBP) must have a negative serum or urine
                       pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human
                       chorionic gonadotropin) within 24 hours prior to the start of study
                       treatment.

                    -  Women must not be breastfeeding.

                    -  WOCBP must agree to follow instructions for method(s) of contraception
                       (Appendix 5) for the duration of study treatment plus 5 half-lives of
                       nivolumab plus 30 days (duration of ovulatory cycle), for a total of 155
                       days post treatment completion. Local laws and regulations may require use
                       of alternative and/or additional contraception methods.

                    -  WOCBP who are continuously not heterosexually active are also exempt from
                       contraceptive requirements, but should still undergo pregnancy testing as
                       described in this section.

                    -  Males who are sexually active with WOCBP must agree to follow instructions
                       for method(s) of contraception (Appendix4) during combination treatment with
                       study treatment BMS-986253 and nivolumab, plus 5 half-lives of nivolumab
                       (∼125 days), plus 90 days (duration of sperm turnover), for a total of 215
                       days post-treatment completion. In addition, male participants must be
                       willing to refrain from sperm donation during this time.

          -  EFFICACY COHORT

               1. Patients with anti-PD1/PDL1 refractory melanoma or RCC.

               2. Patients with 1-4 tumor sites that can be irradiated safely

               3. Patients who have detectable serum IL-8 (> 10 pg/mL) at baseline

               4. Age ≥ 18 years

               5. ECOG performance status 0 or 1

               6. Patients must have normal organ and marrow function as defined above for safety
                  cohort

               7. Patients must have measurable disease, defined as at least one lesion that can be
                  accurately measured in at least one dimension (longest diameter to be recorded
                  for non- nodal lesions and short axis for nodal lesions) as ≥10 mm (≥1 cm) with
                  CT scan, MRI, or calipers by clinical exam

               8. Ability to understand and the willingness to sign a written informed consent
                  document.

        Exclusion Criteria:

          1. Known or suspected CNS metastases, with the following exceptions:

             a) Subjects with controlled brain metastases will be allowed to enroll. Controlled
             brain metastases are defined as no radiographic progression for at least 4 weeks
             following 18 radiation and/or surgical treatment at the time of randomization. b)
             Subjects must be off steroids for at least 2 weeks prior to randomization c) Subjects
             with signs or symptoms of brain metastases are not eligible unless brain metastases
             are ruled out by computed tomography or magnetic resonance imaging.

          2. Medical History and Concurrent Diseases

               -  Patients who are receiving any other investigational agents.

               -  History of allergic reactions attributed to compounds of similar chemical or
                  biologic composition to nivolumab and BMS-986253

               -  Subjects with an active, known or suspected autoimmune disease. Subjects with
                  type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin
                  disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic
                  treatment, or conditions not expected to recur in the absence of an external
                  trigger are permitted to enroll.

               -  Uncontrolled or significant cardiovascular disease including, but not limited to,
                  any of the following:

                  i. Myocardial infarction (MI) or stroke/transient ischemic attack (TIA) within
                  the 6 months prior to consent ii. Uncontrolled angina within the 3 months prior
                  to consent iii. Any history of clinically significant arrhythmias (such as
                  ventricular tachycardia, ventricular fibrillation, torsades de pointes, or poorly
                  controlled atrial fibrillation) iv. QTc prolongation > 480 msec v. History of
                  other clinically significant cardiovascular disease (i.e., cardiomyopathy,
                  congestive heart failure with New York Heart Association [NYHA] functional
                  classification III-IV, pericarditis, significant pericardial effusion,
                  significant coronary stent occlusion, poorly controlled deep venous thrombosis,
                  etc) vi. Cardiovascular disease-related requirement for daily supplemental oxygen
                  vii. History of two or more MIs OR two or more coronary revascularization
                  procedures viii. Subjects with history of myocarditis, regardless of etiology

               -  A confirmed history of encephalitis, meningitis, or uncontrolled seizures in the
                  year prior to informed consent

               -  Subjects with history of life-threatening toxicity related to prior immune
                  therapy (eg. anti-CTLA-4 or any other antibody or drug specifically targeting
                  T-cell co-stimulation or immune checkpoint pathways) except those that are
                  unlikely to re-occur with standard countermeasures (eg, hormone replacement after
                  endocrinopathy).

               -  Subject has been administered prior chemotherapy or immunotherapy at any time,
                  and any with radiation therapy within 4 weeks prior to time of consent or who has
                  not recovered (ie, ≤ Grade 1 or at baseline) from adverse events due to
                  previously administered agent.

                    1. Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and
                       may qualify for the study.

                    2. Subjects with endocrinopathy which is adequately controlled with hormone
                       replacement therapy are an exception to this criterion and may qualify for
                       the study.

               -  If subject underwent major surgery, subject must have recovered adequately from
                  the toxicity and/or complications from the intervention prior to starting
                  therapy.

               -  Subject has a known additional malignancy that is progressing or requires active
                  treatment. Exceptions include basal cell carcinoma of the skin or squamous cell
                  carcinoma of the skin that has undergone potentially curative therapy or in situ
                  cervical cancer.

               -  A known or underlying medical condition that, in the opinion of the investigator
                  could make the administration of study drug hazardous to the subject or could
                  adversely affect the ability of the subject to comply with or tolerate study
                  therapy.

               -  Pregnant women are excluded from this study because of the potential for
                  teratogenic or abortifacient effects. Because there is an unknown but potential
                  risk for adverse events in nursing infants secondary to treatment of the mother,
                  breastfeeding should be discontinued if the mother is treated with the study
                  drugs.

               -  Subjects who are unable to undergo venipuncture and/or tolerate venous access

               -  Evidence of active infection that requires systemic antibacterial, antiviral, or
                  antifungal therapy ≤ 7 days prior to initiation of study drug therapy

               -  Subjects who are on immunosuppressive therapy (systemic steroids 10mg and more
                  daily use)

               -  Prisoners or subjects who are involuntarily incarcerated

               -  Subjects who are compulsorily detained for treatment of either a psychiatric or
                  physical (e.g., infectious disease) illness

               -  Inability to comply with restrictions and prohibited activities and treatments
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Rate of Dose Limiting Toxicities (DLT)
Time Frame:Up to 8 weeks after start of immunotherapeutic treatment
Safety Issue:
Description:The rate of Dose Limiting Toxicities (DLT) that are determined to be definitely, probably or possibly attributed to SBRT or one or both of the immunotherapies. Patients receiving one of more fractions of SBRT are evaluable for DLT. Toxicities include grade 3 or higher adverse events, by organ system, by Common Terminology Criteria for Adverse Events (CTCAE) v5.0.

Secondary Outcome Measures

Measure:Incidence of grade 3 or higher adverse events
Time Frame:Up to 1 year after start of immunotherapeutic treatment
Safety Issue:
Description:Incidence of grade 3 or higher adverse events, by organ system, per CTCAEv5.0, determined to be definitely, probably or possibly attributed to SBRT or one or both of the immunotherapies.
Measure:Objective Response
Time Frame:Up to 3 years
Safety Issue:
Description:The proportion of patients that experience a Complete Response (CR) or Partial Response (PR) per RECIST v1.1. Per RECIST v1.1: Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
Measure:Progression-free survival (PFS)
Time Frame:Up to 3 years
Safety Issue:
Description:The duration of time from first day of treatment until disease progression or date of death from any cause will be estimated with a 90% confidence interval. Progression as defined by RECIST v1.1 for target lesions: Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions). For non-target lesions: Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.
Measure:Overall survival (OS)
Time Frame:Up to 3 years
Safety Issue:
Description:Overall survival (OS) (of the cohort) which is defined as elapsed time from date of first treatment until date of death.
Measure:Local tumor control (RECIST v1.1)
Time Frame:Up to 3 years
Safety Issue:
Description:The total disappearance of the primary tumor and neighboring lymph node metastases without any local recurrence on long-term follow-up, per RECIST version 1.1. Complete response per RECIST v1.1 is the disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to <10 mm.
Measure:Local tumor control (irRECIST)
Time Frame:Up to 3 years
Safety Issue:
Description:The total disappearance of the primary tumor and neighboring lymph node metastases without any local recurrence on long-term follow-up, by immune-related RECIST (irRECIST). Immune Complete Response (iCR) is the complete resolution of non-nodal lesions and < 10 mm short-axis for lymph nodes. No confirmation necessary.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Jason J. Luke, MD

Trial Keywords

  • Anti-PD-1 monoclonal antibody (mAb)
  • Anti-IL-8
  • Stereotactic Body Radiotherapy (SBRT)

Last Updated

March 12, 2021