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A Phase 2 Study of NIR178 in Combination With PDR001 in Patients With Solid Tumors and Non-Hodgkin Lymphoma

NCT03207867

Description:

The purpose of this phase 2 study is to evaluate the efficacy and safety of NIR178 in combination with PDR001 in multiple solid tumors and diffuse large B-cell lymphoma (DLBCL) and further explore schedule variations of NIR178 to optimize immune activation through inhibition of A2aR.

Related Conditions:
  • Breast Carcinoma
  • Colon Carcinoma
  • Diffuse Large B-Cell Lymphoma
  • Head and Neck Carcinoma
  • Melanoma
  • Non-Small Cell Lung Carcinoma
  • Pancreatic Carcinoma
  • Renal Cell Carcinoma
  • Urothelial Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Phase 2 Study of NIR178 in Combination With PDR001 in Patients With Solid Tumors and Non-Hodgkin Lymphoma
  • Official Title: A Phase 2, Multi-center, Open Label Study of NIR178 in Combination With PDR001 in Patients With Selected Advanced Solid Tumors and Non-Hodgkin Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: CNIR178X2201
  • SECONDARY ID: 2017-000241-49
  • NCT ID: NCT03207867

Conditions

  • NSCLC, Non Small Cell Lung Cancer
  • RCC, Renal Cell Cancer
  • Pancreatic Cancer
  • Urothelial Cancer
  • Head and Neck Cancer
  • DLBCL, Diffused Large B Cell Lymphoma
  • MSS, Microsatellite Stable Colon Cancer
  • TNBC, Triple Negative Breast Cancer
  • Melanoma

Interventions

DrugSynonymsArms
NIR178NIR178 + PDR001
PDR001NIR178 + PDR001

Purpose

The purpose of this phase 2 study is to evaluate the efficacy and safety of NIR178 in combination with PDR001 in multiple solid tumors and diffuse large B-cell lymphoma (DLBCL) and further explore schedule variations of NIR178 to optimize immune activation through inhibition of A2aR.

Detailed Description

      The study has four parts: part 1: Multi-arm Bayesian adaptive signal finding design in solid
      tumors and diffuse large B cell lymphoma (DLBCL); part 2: NIR178 schedule exploration in
      NSCLC; part 3: Further evaluation of intermittent dosing schedules of NIR178 in combination
      with PDR001 in additional tumor types, if part 2 identifies an intermittent dosing schedule
      of NIR178 as warranting further exploration; part 4: A separate safety run-in part will be
      conducted in Japan in order to adequately characterize the safety and pharmacokinetic
      profiles of NIR178 as a single-agent.

      Parts 1, 2 and 4 will enroll in parallel. Part 3 will be opened based on the results from
      part 2.

      Patients enrolled in this study will receive NIR178 either BID continuously or based on the
      assigned intermittent schedule within 60 minutes prior to PDR001 infusion. PDR001 will be
      administered via IV infusion over 30 minutes once every 4 weeks. Each treatment cycle is 28
      days. Patients enrolled in the Japanese safety run-in part will receive NIR178 as single
      agent for the first cycle (28 days). If the patients complete cycle 1 without experiencing
      DLTs, they will initiate combination therapy with PDR001 starting cycle 2 onwards, and
      continue at the same dose of NIR178.

      Patients will receive treatment with the combination until disease progression (assessed by
      investigator per immune-related response criteria (irRC) or Cheson 2014, unacceptable
      toxicity, death or discontinuation from study treatment for any other reason (e.g.,
      withdrawal of consent, start of a new anti-neoplastic therapy or at the discretion of the
      investigator), otherwise known as End of Treatment.
    

Trial Arms

NameTypeDescriptionInterventions
NIR178 + PDR001ExperimentalPart 1: all patients will receive NIR178 continuously in combination with PDR001 400mg every 4 weeks. The part 1 will enroll 8 different tumor types.
  • NIR178
  • PDR001
NIR178 BID Intermittent + PDR001ExperimentalThree different dosing schedules of NIR178 will be explored.
  • NIR178
  • PDR001
Part 3ExperimentalInitiation of part 3 will depend on results from parts 1 and 2.
  • NIR178
  • PDR001
Japanese safety run-in partExperimentalTwo different dosing schedules of NIR178 will be explored.
  • NIR178
  • PDR001

Eligibility Criteria

        Inclusion Criteria:

        Male or female patients ≥18 years of age. For Japan only: written consent is necessary both
        from the patient and his/her legal representative if he/she is under the age of 20 years.

        Histologically documented advanced or metastatic solid tumors or lymphomas

          -  Part 1: histologically confirmed renal cell carcinoma (RCC), pancreatic cancer,
             urothelial cancer, head and neck cancer, diffuse large B-cell lymphoma (DLBCL),
             microsatellite stable (MSS) colon cancer, triple negative breast cancer (TNBC) or
             melanoma

          -  Part 2: histologically confirmed diagnosis of advanced/metastatic NSCLC. For those
             with mixed histology, there must be a predominant histology

          -  Part 3: histologically confirmed diagnosis of advanced/metastatic NSCLC and one
             additional tumor type based on emerging data from part 1 of the study.

        Patient (except for those participating in Japanese safety run-in) must have a site of
        disease amenable to biopsy, and be a candidate for tumor biopsy according to the treating
        institution's guidelines. Patient must be willing to undergo a new tumor biopsy at
        screening, and again during therapy on this study.

        o Part 4: Safety run-in part in Japanese patients can enroll any tumor type included in
        part 1 and 2.

        The collection of recent sample is permitted under the following conditions (both must be
        met):

          -  Biopsy was collected ≤ 3 months before 1st dose of study treatment and available at
             the site.

          -  No immunotherapy was given to the patient since collection of biopsy.

        Part 1 - 3 only: Patients (other than those with DLBCL) must previously have received at
        least 1 and no more than 3 prior lines of therapy for their disease, specifically including
        the following, unless considered inappropriate for the patient (e.g. safety concern, label
        contraindication):

          -  Patients with NSCLC must have received a prior platinum-based combination.

          -  Patients with EGFR positive NSCLC with a T790M mutation must have progressed on
             osimertinib or discontinued due to toxicity.

          -  Patients with head and neck cancer must have received a prior platinum-containing
             regimen.

          -  Patients with bladder cancer must have received a prior platinum-containing regimen or
             be ineligible for cisplatin.

          -  Patients with renal cell carcinoma must have received a prior VEGF tyrosine kinase
             inhibitor (TKI).

          -  Patients with MSS colorectal cancer must have received (or be intolerant to) prior
             therapy with fluoropyrimidine-oxaliplatin- and irinotecan- based regimens.

          -  Patients with triple negative breast cancer must have received a prior
             taxane-containing regimen.

        Patients with DLBCL should be limited to those with no available therapies of proven
        clinical benefit

        o Patients should have had prior autologous hematopoietic stem cell transplantation
        (auto-HSCT) or determined to be ineligible for auto-HSCT.

        Patients must not have received prior immunotherapy (previous immune checkpoint inhibitors;
        single agent and/or combination therapy with anti-CTLA-4, anti-PD-1, anti-PD-L1), except
        for NSCLC patients enrolled in part 3 and Japanese safety run-in part.

        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 >20 mm with conventional techniques
        or as >10 mm with spiral computer tomography (CT) scan, Magnetic Resonance Imaging (MRI),
        or calipers by clinical exam.

        Other protocol-defined inclusion criteria may apply.

        Exclusion Criteria:

        Ongoing or prior treatment with A2aR inhibitors. Patients previously treated with A2aR
        inhibitors for non-oncologic indications (e.g. Parkinson's disease) may be considered for
        enrollment on a case by case basis.

        Current or prior use of immunosuppressive medication within 28 days before the first dose
        of PDR001, with the exception of intranasal/inhaled corticosteroids or systemic
        corticosteroids at physiological doses (not exceeding equivalent of 10 mg/day of
        prednisone) History of another primary malignancy except for:

          -  Malignancy treated with curative intent and with no known active disease ≥2 years
             before the first dose of study drug and of low potential risk for recurrence

          -  Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of
             disease

          -  Adequately treated carcinoma in situ without evidence of disease Active or prior
             documented autoimmune disease within the past 2 years. Patients with vitiligo, Grave's
             disease, or psoriasis not requiring systemic treatment (within the past 2 years) are
             not excluded.

        More than 3 prior lines of therapy except for Japanese safety run-in part. History of
        interstitial lung disease or non-infectious pneumonitis Participation in another clinical
        study with an investigational product during the last 21 days prior to starting on
        treatment.

        Other protocol-defined exclusion criteria may apply.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Determine the overall response rate
Time Frame:Every 8 weeks for first 40 weeks
Safety Issue:
Description:Response assessed by RECIST v1.1 (for solid tumors) or Cheson (for DLBCL)

Secondary Outcome Measures

Measure:Determine the disease control rate (DCR)
Time Frame:Baseline
Safety Issue:
Description:Proportion of patients with a best overall response of CR or PR or SD
Measure:Determine the duration of response (DoR)
Time Frame:Baseline
Safety Issue:
Description:Time from first documented response to disease progression
Measure:Determine the overall survival rate (OR)
Time Frame:Every 12 weeks until end of study for at least 24 months from the start date of the study treatment
Safety Issue:
Description:Time from start of treatment to date of death due to any reason
Measure:Progression free survival (PFS)
Time Frame:Baseline
Safety Issue:
Description:Time from start of treatment to date of the first documented progression or death in months
Measure:Safety and tolerability of the NIR178 and PDR001 combination
Time Frame:Date of consent to end of study (An average of 24 months)
Safety Issue:
Description:Type, frequency, and severity of AEs and SAEs; Frequency of dose interruptions, reductions and discontinuation, Dose intensity
Measure:Characterize changes in the immune infiltrate in tumors
Time Frame:Screening
Safety Issue:
Description:Change from baseline in TILs by immunohistochemistry (IHC) (such as CD8)
Measure:Presence and/or concentration of anti-PDR001 antibodies
Time Frame:Starting from the first dose of study treatment to Cycle 6 Day 1
Safety Issue:
Description:Presence and/or concentration of anti-PDR001 antibodies
Measure:Pharmacokinetics: Area under plasma concentration versus time curve (AUC) (NIR178)
Time Frame:Starting from the first dose of study treatment to Cycle 6 Day 1
Safety Issue:
Description:Plasma concentration time profiles of NIR178 and its metabolites
Measure:Pharmacokinetics: Area under the plasma concentration versus time curve (AUC) (PDR001)
Time Frame:End of treatment and as needed (an average of 6 months)
Safety Issue:
Description:Plasma concentration time profiles of PDR001
Measure:Plasma concentration Vs Time profiles (NIR178)
Time Frame:End of treatment and as needed (an average of 6 months)
Safety Issue:
Description:Plasma concentration time profiles of NIR178
Measure:Plasma concentration Vs Time profiles (PDR001)
Time Frame:End of treatment and as needed (an average of 6 months)
Safety Issue:
Description:Plasma concentration time profiles of PDR001
Measure:Peak plasma concentration- Cmax (NIR178)
Time Frame:End of treatment and as needed (an average of 6 months)
Safety Issue:
Description:Plasma concentration time profiles of NIR178
Measure:Peak plasma concentration- Cmax (PDR001)
Time Frame:End of treatment and as needed (an average of 6 months)
Safety Issue:
Description:Plasma concentration time profiles of PDR001
Measure:Time of maximum concentration observed- Tmax (NIR178)
Time Frame:End of treatment and as needed (an average of 6 months)
Safety Issue:
Description:Plasma concentration time profiles of NIR178
Measure:Time of maximum concentration observed- Tmax (PDR001)
Time Frame:End of treatment and as needed (an average of 6 months)
Safety Issue:
Description:Plasma concentration time profiles of PDR001
Measure:Determine the disease control rate (DCR)
Time Frame:Every 8 weeks for first 40 weeks
Safety Issue:
Description:Proportion of patients with a best overall response of CR or PR or SD
Measure:Determine the disease control rate (DCR)
Time Frame:Every 12 weeks after the first 40 weeks until disease progression
Safety Issue:
Description:Proportion of patients with a best overall response of CR or PR or SD
Measure:Determine the duration of response (DoR)
Time Frame:Until study discontinuation (an average of 6 months)
Safety Issue:
Description:Time from first documented response to disease progression
Measure:Determine the duration of response (DoR)
Time Frame:Every 8 weeks for first 40 weeks
Safety Issue:
Description:Time from first documented response to disease progression
Measure:Progression free survival (PFS)
Time Frame:Until study discontinuation (an average of 6 months)
Safety Issue:
Description:Time from start of treatment to date of the first documented progression or death in months
Measure:Progression free survival (PFS)
Time Frame:Every 8 weeks for first 40 weeks
Safety Issue:
Description:Time from start of treatment to date of the first documented progression or death in months
Measure:Characterize changes in the immune infiltrate in tumors
Time Frame:Cycle 6 Day 1
Safety Issue:
Description:Change from baseline in TILs by immunohistochemistry (IHC) (such as CD8)
Measure:Characterize changes in the immune infiltrate in tumors
Time Frame:Cycle 1 Day 8
Safety Issue:
Description:Change from baseline in TILs by immunohistochemistry (IHC) (such as CD8)
Measure:Characterize changes in the immune infiltrate in tumors
Time Frame:Cycle 3 Day 1
Safety Issue:
Description:Change from baseline in TILs by immunohistochemistry (IHC) (such as CD8)
Measure:Presence and/or concentration of anti-PDR001 antibodies
Time Frame:End of treatment and as needed (an average of 6 months)
Safety Issue:
Description:Presence and/or concentration of anti-PDR001 antibodies
Measure:Pharmacokinetics: Area under plasma concentration versus time curve (AUC) (NIR178)
Time Frame:End of treatment and as needed (an average of 6 months)
Safety Issue:
Description:Plasma concentration time profiles of NIR178 and its metabolites
Measure:Plasma concentration Vs Time profiles (NIR178)
Time Frame:Starting from the first dose of study treatment to Cycle 6 Day 1
Safety Issue:
Description:Plasma concentration time profiles of NIR178
Measure:Plasma concentration Vs Time profiles (PDR001)
Time Frame:Starting from the first dose of study treatment to Cycle 6 Day 1
Safety Issue:
Description:Plasma concentration time profiles of PDR001
Measure:Peak plasma concentration- Cmax (NIR178)
Time Frame:Starting from the first dose of study treatment to Cycle 6 Day 1
Safety Issue:
Description:Plasma concentration time profiles of NIR178
Measure:Peak plasma concentration- Cmax (PDR001)
Time Frame:Starting from the first dose of study treatment to Cycle 6 Day 1
Safety Issue:
Description:Plasma concentration time profiles of PDR001
Measure:Time of maximum concentration observed- Tmax (NIR178)
Time Frame:Starting from the first dose of study treatment to Cycle 6 Day 1
Safety Issue:
Description:Plasma concentration time profiles of NIR178
Measure:Time of maximum concentration observed- Tmax (PDR001)
Time Frame:Starting from the first dose of study treatment to Cycle 6 Day 1
Safety Issue:
Description:Plasma concentration time profiles of PDR001
Measure:Determine the disease control rate (DCR)
Time Frame:Until study discontinuation (an average of 6 months)
Safety Issue:
Description:Proportion of patients with a best overall response of CR or PR or SD
Measure:Determine the duration of response (DoR)
Time Frame:Every 12 weeks after the first 40 weeks until disease progression
Safety Issue:
Description:Proportion of patients with a best overall response of CR or PR or SD
Measure:Progression free survival (PFS)
Time Frame:Every 12 weeks after the first 40 weeks until disease progression
Safety Issue:
Description:Time from start of treatment to date of the first documented progression or death in months

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Novartis Pharmaceuticals

Trial Keywords

  • Immunotherapy, A2aR, PDR001, NIR178, NSCLC, solid tumors

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