Clinical Trials /

Personalized Immunotherapy in Patients With Recurrent /Metastatic SCCHN That Have Progressed on Prior Immunotherapy

NCT04326257

Description:

In this Phase II trial of personalized immunotherapy in R/M HNSCC, gene expression of LAG3 and CTLA4 by RNA seq will be determined to select the appropriate agent (Ipilimumab or Relatlimab) to add to Nivolumab in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M HNSCC) who have failed prior immunotherapy with anti-PD-1 or PD-L1 mAb therapy. The agent, either Ipilimumab or Relatlimab will be chosen based on the highest relevant immune gene expression (CTLA4 or LAG-3) as long as the minimum difference required is met.

Related Conditions:
  • Head and Neck Squamous Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Personalized Immunotherapy in Patients With Recurrent /Metastatic SCCHN That Have Progressed on Prior Immunotherapy
  • Official Title: A Phase II Trial of Personalized Immunotherapy in Patients With Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck That Have Progressed on Prior Immunotherapy

Clinical Trial IDs

  • ORG STUDY ID: HCC 18-156
  • NCT ID: NCT04326257

Conditions

  • Squamous Cell Carcinoma of the Head and Neck

Interventions

DrugSynonymsArms
Nivolumab+RelatlimabNivolumab: OPDIVO/ BMS-936558/ MDX1106/ ONO-4538;, Relatlimab: BMS-986016Nivolumab+Relatlimab
Nivolumab+IpilimumabNivolumab: OPDIVO/ BMS-936558/ MDX1106/ ONO-4538, Ipilimumab: YERVOY/ BMS-734016/ MDX-010Nivolumab+Ipilimumab

Purpose

In this Phase II trial of personalized immunotherapy in R/M HNSCC, gene expression of LAG3 and CTLA4 by RNA seq will be determined to select the appropriate agent (Ipilimumab or Relatlimab) to add to Nivolumab in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M HNSCC) who have failed prior immunotherapy with anti-PD-1 or PD-L1 mAb therapy. The agent, either Ipilimumab or Relatlimab will be chosen based on the highest relevant immune gene expression (CTLA4 or LAG-3) as long as the minimum difference required is met.

Detailed Description

      In this Phase II non-randomized trial, n=40 eligible patients will have tumor tissue (core or
      excisional/incisional) for gene expression of LAG3 and CTLA4 via RNA seq per OmniSeq Immune
      Report Card to determine which drug (either Relatlimab or Ipilimumab) will be added to
      Nivolumab for treatment. The patient will then receive the prescribed therapy continuously
      for up to 24 cycles (1 cycle = 4 weeks of treatment). The drug to be added to Nivolumab will
      be based on which relevant gene has the highest expression as long as the minimum difference
      required is met. If the minimum difference is not met than a patient will be randomized to
      either Nivolumab plus Relatlimab or Nivolumab plus Ipilimumab.

      The patient will then receive the prescribed therapy continuously for up to 24 cycles (1
      cycle = 4 weeks of treatment) with repeat imaging prior to every 3rd cycle until progression
      of disease. Response, evaluated by RECIST 1.1, with modifications to allow for continued
      therapy until progressive disease is confirmed if the patient is clinically stable, will be
      used in the trial. If the patient has confirmed progression the patient may be eligible to
      undergo a second biopsy and second treatment on trial. If these criteria are met the patient
      will then be treated with this new combination with repeat imaging prior to every 3rd cycle
      as per initial treatment, until progression of disease.
    

Trial Arms

NameTypeDescriptionInterventions
Nivolumab+RelatlimabExperimentalNivolumab will be dosed 480mg IV q 4 weeks and Relatlimab 160mg IV q 4 One cycle is defined as 4 weeks of treatment and both drugs are given on the same day. Patients will receive the prescribed therapy continuously for up to 24 cycles until progression of disease or adverse event(s) requiring treatment discontinuation.
  • Nivolumab+Relatlimab
Nivolumab+IpilimumabExperimentalNivolumab will be dosed at 3mg/kg IV q 2 weeks and Ipilimumab 1mg/kg IV q 6 weeks. Patients will receive four doses of Ipilimumab and the last dosage of Nivolumab 3mg/kg IV q 2 weeks will be given at the time of the 4th dose of Ipilimumab, followed 2 weeks later by Nivolumab 480 mg IV q 4 weeks. A cycle of therapy will be defined as 4 weeks of treatment. The patient will receive the prescribed therapy continuously for up to 24 cycles until progression of disease or adverse event(s) requiring treatment discontinuation.
  • Nivolumab+Ipilimumab

Eligibility Criteria

        Inclusion Criteria:

          1. Recurrent and/or Metastatic squamous cell carcinoma of the head and neck that is not
             amenable to therapy with curative intent. Patients who refuse salvage surgery or
             radiation for recurrence are potentially eligible.

          2. Failure of prior immunotherapy as defined as:

               1. Progression of disease on anti-PD-1 mAb or anti-PD-L1 mAb treatment in the R/M
                  setting. The anti-PD-1/PDL1 antibody treatment must be the most recent preceding
                  therapy prior to enrollment with progression of disease on anti-PD-1/PD-L1
                  antibody defined according to iRECIST criteria (Seymour et al, Lancet Oncology
                  2017; 18: e14352).

               2. Both patients that have received platinum based chemotherapy prior or have not
                  yet received platinum based chemotherapy are eligible.

          3. ECOG performance status of 0-1

          4. Have at least one measurable area of disease (Target Lesion) based on RECIST 1.1.

          5. Provide adequate tissue (core or incisional/excisional biopsy) prior to starting study
             for analysis for gene expression of LAG3 and CTLA4 per OmniSeq Immune Report Card. FNA
             is not adequate. Archival tissue can only be used if it was obtained in the
             recurrent/metastatic setting and there has been no subsequent cancer treatment after
             that tissue was obtained.

          6. Life expectancy of at least 12 weeks based on investigator estimate.

          7. Age ≥ 18 years old

          8. LVEF assessment with documented LVEF ≥50% by either TTE or MUGA (TTE preferred test)
             within 6 months from first study drug administration

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

               -  absolute neutrophil count ≥1,500/mcL

               -  platelets ≥100,000/mcL

               -  total bilirubin ≤ institutional upper limit of normal (ULN)

               -  AST(SGOT)/ALT(SGPT) ≤2.5 x institutional ULN

               -  creatinine ≤ institutional ULN

             OR

             - glomerular filtration rate ≥40 mL/min/1.73 m2 for patients with creatinine levels.
             (GFR) above institutional normal.

         10. Female subjects of childbearing potential should have a negative urine or serum
             pregnancy within 1 days prior to receiving the first dose of study medication. If the
             urine test is positive or cannot be confirmed as negative, a serum pregnancy test will
             be required.

         11. Female subjects of childbearing potential should be willing to use 1 methods of birth
             control or abstain from heterosexual activity for the course of the study through 5
             months after the last dose of study medication. Women of childbearing potential are
             those who have not been surgically sterilized or have not been free from menses for >
             1 year.

         12. Male subjects should agree to use an adequate method of contraception starting with
             the first dose of study therapy through 7 months after the last dose of study therapy.

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

        Exclusion Criteria:

          1. SCC of salivary gland origin or cutaneous SCC of the head and neck. HNSCC of unknown
             origin ARE eligible.

          2. Patients who received Ipilimumab or Relatlimab in the recurrent/metastatic setting
             will be excluded.

          3. Is currently participating in or has participated in a study of an investigational
             agent or used an investigational device within 2 weeks of the first dose of treatment.

          4. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy
             (equivalent of >10 mg of prednisone) or any other form of immunosuppressive therapy
             within 7 days prior to the first dose of trial treatment.

          5. Has had a prior monoclonal antibody, chemotherapy, or targeted small molecule therapy
             within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at
             baseline) from adverse events due to agents administered more than 4 weeks earlier
             (alopecia is an exception). Note: Subjects with ≤ Grade 2 neuropathy, ototoxicity,
             hypothyroidism or hyperthyroidism, are an exception to this criterion and qualify for
             the study.

          6. History of other malignancy within 3 years with the exception of prior HNSCC,
             adequately treated basal cell or squamous cell skin cancer, or carcinoma of the
             cervix.

          7. Has an active autoimmune disease requiring systemic immunosuppressive treatment within
             the past 3 months. Subjects with vitiligo, Grave's disease, or psoriasis not requiring
             systemic therapy or resolved childhood asthma/atopy would be an exception to this
             rule. Subjects that require intermittent use of bronchodilators or local steroid
             injections would not be excluded from the study. Subjects with hypothyroidism stable
             on hormone replacement or Sjorgen's syndrome will not be excluded from the study.

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

               1. Myocardial infarction (MI) or stroke/transient ischemic attack (TIA) within the 6
                  months prior to consent;

               2. Uncontrolled angina within the 3 months prior to consent;

               3. Any history of clinically significant arrhythmias (such as ventricular
                  tachycardia, ventricular fibrillation, torsades de pointes, or poorly controlled
                  atrial fibrillation);

               4. QTc prolongation > 480 msec;

               5. 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.);

               6. Cardiovascular disease-related requirement for daily supplemental oxygen

               7. History of two or more MIs OR two or more coronary revascularization procedures

               8. Subjects with history of myocarditis, regardless of etiology.

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

         10. Subjects with history of life-threatening toxicity related to prior immune therapy
             (eg. anti-CTLA-4 or anti-PD-1/PD-L1 treatment 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).

         11. Troponin T (TnT) or I (TnI) > 2 × institutional ULN. Subjects with TnT or TnI levels
             between > 1 to 2 × ULN will be permitted if repeat levels within 24 hours are ≤1 x
             ULN. If TnT or TnI levels are >1 to 2 × ULN within 24 hours, the subject may undergo a
             cardiac evaluation and be considered for treatment based on the discretion of the PI.
             When repeat levels within 24 hours are not available, a repeat test should be
             conducted as soon as possible. If TnT or TnI repeat levels beyond 24 hours are < 2 x
             ULN, the subject may undergo a cardiac evaluation and be considered for treatment,
             based on the discretion of the PI.

         12. Has a history of non-infectious pneumonitis that required steroids, evidence of
             interstitial lung disease, or currently active non-infectious pneumonitis.

         13. Has a history or current evidence of any condition, therapy, or laboratory abnormality
             that might confound the results of the trial, interfere with the subject's
             participation for the full duration of the trial, or is not in the best interest of
             the subject to participate, in the opinion of the treating investigator.

         14. Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial.

         15. Is pregnant or breastfeeding or expecting to conceive or father children within the
             projected duration of the trial, starting with the screening visit through 24 weeks
             after the last dose of trial treatment.

         16. Has a history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

         17. Has active Hepatitis B or Hepatitis C

         18. Has a history of a solid organ transplant.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Probability of Objective Response (OR)
Time Frame:From start of treatment, up to 36 months
Safety Issue:
Description:The estimated probability of response to therapy in patients who have progressed on prior immunotherapy. Per Response Evaluation Criteria in Solid Tumors (RECIST v1.1) Complete Response (CR) is disappearance of all target and non-target lesions; Partial Response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

Secondary Outcome Measures

Measure:Disease Control Rate (DCR)
Time Frame:From start of treatment, up to 36 months
Safety Issue:
Description:The estimated Disease Control Rate (DCR) in patients who have progressed on prior immunotherapy. Per Response Evaluation Criteria in Solid Tumors (RECIST v1.1) Complete Response (CR) is disappearance of all target and non-target lesions; Partial Response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters; Stable Disease (SD) is neither sufficient decrease (target lesions) to qualify as a PR or sufficient increase to qualify as PD. Incomplete Response/Stable Disease (SD) is the persistence of one or more non-target lesions.
Measure:Progression-free Survival (PFS)
Time Frame:From start of treatment up to 36 months
Safety Issue:
Description:The length of time from the start of treatment that patients live with disease that does not progress per Response Evaluation Criteria in Solid Tumors (RECIST v1.1) in patients who have progressed on prior immunotherapy. Per RECIST, Progressive Disease (PD) is defined as at least a 20% increase in the sum of the diameters of target lesions compared to baseline sum of target lesions, or any new lesions.It also includes the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.
Measure:Overall Survival (OS)
Time Frame:From start of treatment, up to 36 months
Safety Issue:
Description:The length of time from the start of treatment that patients remain alive, in patients who have progressed on prior immunotherapy.
Measure:Adverse Events per Common Terminology Criteria for Adverse Events (CTCAE) v5.0
Time Frame:From start of treatment, up to 36 months
Safety Issue:
Description:Adverse Events possibly, probably or definitely related to study treatment per Common Terminology Criteria for Adverse Events (CTCAE) v5.0 experienced by all patients.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Dan Zandberg

Trial Keywords

  • nivolumab
  • Relatlimab
  • Ipilimumab
  • immunotherapy
  • anti-PD-1
  • anti-PD-L1
  • RECIST 1.1
  • recurrent cancer
  • metastatic cancer
  • tumor microenvironment analysis
  • LAG-3
  • CTLA-4

Last Updated

April 5, 2020