Clinical Trials /

A Study of PDR001 in Combination With LCL161, Everolimus or Panobinostat

NCT02890069

Description:

The purpose of this study is to combine the PDR001 checkpoint inhibitor with several agents with immunomodulatory activity to identify the doses and schedule for combination therapy and to preliminarily assess the safety, tolerability, pharmacological and clinical activity of these combinations.

Related Conditions:
  • Breast Carcinoma
  • Colorectal Carcinoma
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Study of PDR001 in Combination With LCL161, Everolimus or Panobinostat
  • Official Title: Phase Ib, Open-label, Multi-center Study to Characterize the Safety, Tolerability and Pharmacodynamics (PD) of PDR001 in Combination With LCL161, Everolimus (RAD001) or Panobinostat (LBH589)

Clinical Trial IDs

  • ORG STUDY ID: CPDR001X2102
  • NCT ID: NCT02890069

Conditions

  • Colorectal Cancer
  • Non-small Cell Lung Carcinoma (Adenocarcinoma)
  • Triple Negative Breast Cancer

Interventions

DrugSynonymsArms
LCL161CRC - PDR001 + LCL161
EverolimusRAD001CRC - PDR001+ Everolimus
PanobinostatLBH589CRC - PDR001 + Panobinostat

Purpose

The purpose of this study is to combine the PDR001 checkpoint inhibitor with several agents with immunomodulatory activity to identify the doses and schedule for combination therapy and to preliminarily assess the safety, tolerability, pharmacological and clinical activity of these combinations.

Detailed Description

Trial Arms

NameTypeDescriptionInterventions
CRC - PDR001 + LCL161Experimental
    • LCL161
    NSCLC - PDR001 + LCL161Experimental
      • LCL161
      TNBC - PDR001 + LCL161Experimental
        • LCL161
        CRC - PDR001+ EverolimusExperimental
            • Everolimus
          NSCLC - PDR001+ EverolimusExperimental
              • Everolimus
            TNBC - PDR001+ EverolimusExperimental
                • Everolimus
              CRC - PDR001 + PanobinostatExperimental
                    • Panobinostat
              NSCLC - PDR001 + PanobinostatExperimental
                    • Panobinostat
              TNBC - PDR001 + PanobinostatExperimental
                    • Panobinostat

              Eligibility Criteria

              Inclusion Criteria:

              - Written informed consent prior to any procedure

              - Patients with advanced/metastatic cancer, with measurable disease as determined by RECIST version 1.1, who have progressed despite standard therapy or are intolerant to SOC, or for whom no standard therapy exists. Patients must fit into one of the following groups:

              CRCNSCLC • TNBC

              - ECOG ≤ 2

              - Patient must have a site of disease for biopsy, and be a candidate for tumor biopsy according to the institution's guidelines. Patient must be willing to undergo a new tumor biopsy at screening, and again during therapy on this study.

              - Prior therapy with PD-1/PDL-1 inhibitors is allowed provided any toxicity attributed to prior PD-1- or PD-L1-directed therapy did not lead to discontinuation of therapy.

              Exclusion Criteria:

              - Presence of symptomatic central nervous system (CNS) metastases, or CNS metastases that require local CNS-directed therapy within prior 2 weeks.

              - History of severe hypersensitivity reactions to other mAbs.

              - Out of range lab values as defined in protocol

              - Impaired cardiac function or clinically significant cardiac disease

              - Active, known or suspected autoimmune disease

              - Human Immunodeficiency Virus (HIV), or active Hepatitis C (HCV) virus. Escalation: active Hepatitis B (HBV); Expansion: Patients with Chronic HBV currently on medication will not be excluded.

              - Impairment of gastrointestinal (GI) function

              - Malignant disease, other than that being treated in this study

              - Systemic anti-cancer therapy within 2 weeks of the first dose of study treatment. For cytotoxic agents that have major delayed toxicity and CTLA-4 antagonists, washout period is 6 weeks.

              - Active infection requiring systemic antibiotic therapy.

              - Patients requiring chronic treatment with systemic steroid therapy, other than replacement dose steroids.

              - Patients receiving systemic treatment with any immunosuppressive medication.

              - Major surgery within 2 weeks of the first dose of study treatment

              - Radiotherapy within 2 weeks of the first dose of study drug

              - Participation in an interventional, investigational study within 2 weeks of the first dose of study treatment.

              - Presence of ≥ CTCAE grade 2 toxicity (except alopecia, peripheral neuropathy and ototoxicity, which are excluded if ≥ CTCAE grade 3) due to prior therapy.

              Additional exclusion criteria for PDR001/LCL161

              - Patients requiring medications metabolized through CYP3A4/5 and have a narrow therapeutic index or medications that are CYP3A4 substrates that cause QT prolongation

              - Patients requiring treatment with strong CYP2C8 inhibitors

              Additional exclusion criteria for PDR001/Everolimus

              - Patients requiring treatment with moderate CYP3A4 inhibitors

              - Patients requiring treatment with a strong CYP3A4 inhibitor or inducer

              Additional exclusion criteria for PDR001/Panobinostat-

              - Patient who received DAC inhibitors

              - Patient needing valproic acid during the study or within 5 days prior to first dose

              - Patients requiring medications that are sensitive CYP2D6 substrates or are anti-arrhythmic drugs/QT-prolonging drugs

              - Patients requiring a strong inhibitor or inducer of CYP3A4

              - Clinically significant, uncontrolled heart disease and/or recent cardiac event within 6 months prior to study

              - Unresolved diarrhea ≥ CTCAE grade 2 or a medical condition associated with chronic diarrhea

              - Taking medications with QT prolongation risk or interval or inducing Torsade de pointes

              Other protocol-defined inclusion exclusion criteria may apply.

              Maximum Eligible Age:N/A
              Minimum Eligible Age:18 Years
              Eligible Gender:All
              Healthy Volunteers:No

              Primary Outcome Measures

              Measure:Phase 1: Incidence of dose limiting toxicities (DLTs)
              Time Frame:During the first two cycles
              Safety Issue:
              Description:cycle = 28 days

              Secondary Outcome Measures

              Measure:Quantification of Tumor Infiltrating Lymphocytes (TILs) by Hematoxylin
              Time Frame:Baseline and approximately after 2 cycles of treatment and at disease progression (an average of 6 months)
              Safety Issue:
              Description:cycle = 28 days
              Measure:Changes from baseline in ECG parameters
              Time Frame:Baseline and end of treatment, an average of 6 months
              Safety Issue:
              Description:
              Measure:Best overall response (BOR)
              Time Frame:T1: Every 2 cycles until the start of T2; T2: every 2 cycles till cycle 5, and every 3 cycles till the patient progresses or is withdrawn from study, an average of 6 months
              Safety Issue:
              Description:cycle = 28 days T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2
              Measure:Time to reach max concentration (Tmax) for PDR001
              Time Frame:Cycle 1 through cycle 6 in treatment period 1 and 2, an average of 6 months
              Safety Issue:
              Description:T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2
              Measure:Presence of anti-PDR001 antibodies
              Time Frame:Cycle 1 through cycle 6 in treatment period 1 and 2, an average of 6 months
              Safety Issue:
              Description:T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2
              Measure:Progression free survival (PFS) per RECIST v1.1
              Time Frame:T1: Every 2 cycles until the start of T2; T2: every 2 cycles till cycle 5, and every 3 cycles till the patient progresses or is withdrawn from study, an average of 6 months
              Safety Issue:
              Description:cycle = 28 days T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2
              Measure:Treatment Free Survival (TFS)
              Time Frame:T1: Every 2 cycles until the start of T2; T2: every 2 cycles till cycle 5, and every 3 cycles till the patient progresses or is withdrawn from study, an average of 6 months
              Safety Issue:
              Description:cycle = 28 days T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2
              Measure:Maximum and minimum plasma concentrations of LCL161 (Cmax and Cmin)
              Time Frame:Cycle 1 through cycle 6 in treatment period 1 and 2, an average of 6 months
              Safety Issue:
              Description:T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2
              Measure:Maximum and minimum Plasma concentrations of everolimus (Cmax and Cmin)
              Time Frame:Cycle 1 through cycle 6 in treatment period 1 and 2, an average of 6 months
              Safety Issue:
              Description:T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2
              Measure:Maximum and minimum plasma concentrations of panobinostat (Cmax and Cmin)
              Time Frame:Cycle 1 through cycle 6 in treatment period 1 and 2, an average of 6 months
              Safety Issue:
              Description:T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2
              Measure:Concentration of anti-PDR001 antibodies
              Time Frame:Cycle 1 through cycle 6 in treatment period 1 and 2, an average of 6 months
              Safety Issue:
              Description:T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2
              Measure:Characterization of TILs and myeloid cell infiltrate by IHC (such as CD8, FoxP3 and myeloid markers as appropriate)
              Time Frame:Baseline and approximately after 2 cycles of treatment and at disease progression (an average of 6 months)
              Safety Issue:
              Description:Cycle = 28 days
              Measure:Quantification of Tumor Infiltrating Lymphocytes (TILs) by eosin (H&E) stain
              Time Frame:Baseline and approximately after 2 cycles of treatment and at disease progression (an average of 6 months)
              Safety Issue:
              Description:cycle = 28 days
              Measure:Maximum and minimum serum concentration of PDR001 (Cmax and Cmin)
              Time Frame:Cycle 1 through cycle 6 in treatment period 1 and 2, an average of 6 months
              Safety Issue:
              Description:T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2
              Measure:Area under the concentration-time curve calculated to the last concentration point (AUClast) for PDR001, as applicable
              Time Frame:Cycle 1 through cycle 6 in treatment period 1 and 2, an average of 6 months
              Safety Issue:
              Description:T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2
              Measure:Progression free survival (PFS) per irRC
              Time Frame:T1: Every 2 cycles until the start of T2; T2: every 2 cycles till cycle 5, and every 3 cycles till the patient progresses or is withdrawn from study, an average of 6 months
              Safety Issue:
              Description:cycle = 28 days T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2
              Measure:Area under the concentration-time curve calculated to the last concentration point (AUClast) for LCL161, as applicable
              Time Frame:Cycle 1 through cycle 6 in treatment period 1 and 2, an average of 6 months
              Safety Issue:
              Description:T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2
              Measure:Time to reach max concentration (Tmax) for LCL161
              Time Frame:Cycle 1 through cycle 6 in treatment period 1 and 2, an average of 6 months
              Safety Issue:
              Description:T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2
              Measure:Time to reach max concentration (Tmax) for Everolimus
              Time Frame:Cycle 1 through cycle 6 in treatment period 1 and 2, an average of 6 months
              Safety Issue:
              Description:Cycle 1 through cycle 6 in treatment period 1 and 2, an average of 6 months
              Measure:Time to reach max concentration (Tmax) for Panobinostat
              Time Frame:Cycle 1 through cycle 6 in treatment period 1 and 2, an average of 6 months
              Safety Issue:
              Description:T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2
              Measure:Area under the concentration-time curve calculated to the last concentration point (AUClast) for Everolimus, as applicable
              Time Frame:Cycle 1 through cycle 6 in treatment period 1 and 2, an average of 6 months
              Safety Issue:
              Description:T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2
              Measure:Area under the concentration-time curve calculated to the last concentration point (AUClast) for Panobinostat, as applicable
              Time Frame:Cycle 1 through cycle 6 in treatment period 1 and 2, an average of 6 months
              Safety Issue:
              Description:T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2

              Details

              Phase:Phase 1
              Primary Purpose:Interventional
              Overall Status:Recruiting
              Lead Sponsor:Novartis Pharmaceuticals

              Trial Keywords

              • PDR001
              • CRC
              • TNBC
              • NSCLC
              • Immunomodulation
              • Biomarkers
              • Bayesian logistic regression model

              Last Updated

              February 2, 2017