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, Renal Cell Carcinoma

Interventions

DrugSynonymsArms
PDR001CRC - PDR001 + LCL161
LCL161CRC - PDR001 + LCL161
EverolimusRAD001CRC - PDR001+ Everolimus
PanobinostatLBH589CRC - PDR001 + Panobinostat
QBM076CRC - PDR001 + QBM076
HDM201CRC - PDR001 + HDM201

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.

Trial Arms

NameTypeDescriptionInterventions
CRC - PDR001 + LCL161ExperimentalEnrollment to this combination arm is closed to further enrollment.
  • PDR001
  • LCL161
NSCLC - PDR001 + LCL161ExperimentalEnrollment to this combination arm is closed to further enrollment.
  • PDR001
  • LCL161
TNBC - PDR001 + LCL161ExperimentalEnrollment to this combination arm is closed to further enrollment.
  • PDR001
  • LCL161
CRC - PDR001+ EverolimusExperimentalEnrollment to this combination arm is closed to further enrollment.
  • PDR001
  • Everolimus
NSCLC - PDR001+ EverolimusExperimentalEnrollment to this combination arm is closed to further enrollment.
  • PDR001
  • Everolimus
TNBC - PDR001+ EverolimusExperimentalEnrollment to this combination arm is closed to further enrollment.
  • PDR001
  • Everolimus
CRC - PDR001 + PanobinostatExperimentalEnrollment to this combination arm is closed to further enrollment.
  • PDR001
  • Panobinostat
NSCLC - PDR001 + PanobinostatExperimentalEnrollment to this combination arm is closed to further enrollment.
  • PDR001
  • Panobinostat
TNBC - PDR001 + PanobinostatExperimentalEnrollment to this combination arm is closed to further enrollment.
  • PDR001
  • Panobinostat
CRC - PDR001 + QBM076ExperimentalEnrollment to this combination arm is closed to further enrollment.
  • QBM076
TNBC - PDR001 + QBM076ExperimentalEnrollment to this combination arm is closed to further enrollment.
  • QBM076
NSCLC- PDR001 + QBM076ExperimentalEnrollment to this combination arm is closed to further enrollment.
  • QBM076
CRC - PDR001 + HDM201ExperimentalDose escalation completed, expansion arm.
  • HDM201
RCC - PDR001 + HDM201ExperimentalDose escalation completed, expansion arm.
  • HDM201

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• RCC

          -  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.

          -  Patients with known hypersensitivity to any of the components of an investigational
             treatment will be excluded from participation in the corresponding arm but are
             eligible for participation in other study arm; Patients that have a history of
             hypersensitivity to rapamycin derivatives will be excluded from participation in the
             everolimus arm

          -  History of or current drug-induced interstitial lung disease or pneumonitis grade ≥2

          -  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 washout period is 6 weeks; prior
             immunotherapy - washout is 4 weeks

          -  Active infection requiring systemic antibiotic therapy.

          -  Patients requiring chronic treatment with systemic steroid therapy, other than
             replacement dose steroids or treatment with low, stable dose of steroid (<10 mg/day
             prednisone or equivalent) for stable CNS metastatic disease.

          -  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.

          -  Use of hematopoietic colony stimulating growth factors </= 3 weeks prior to first dose

        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 areCYP2D6
             substrates with a narrow therapeutic index or are anti-arrhythmic drugs/drugs with
             QT-prolongation risks

          -  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

        Additional exclusion criteria for PDR001/QBM076-

          -  Patients requiring medications that are strong inducers or strong inhibitors of CYP3A4

          -  Patients requiring medications with narrow therapeutic index CYP3A4 substrates

          -  Women using any form of hormonal contraception (oral, injected, implanted,
             transdermal) will be excluded (unless they are willing to switch to another effective
             form of contraception under their physician's guidance)

        Additional exclusion criteria for PDR001/HDM201-

          -  Prior treatment with compounds with the same mode of action as proposed for HDM201,
             i.e. an inhibition of the interaction of TP53 with HDM2, e.g. RG7112 or CGM097

          -  Patients who require the following treatments moderate to strong CYP3A4 inhibitors;
             any substrates of CYP3A4/5 with a narrow therapeutic index

          -  Moderate to strong CYP3A4 inducers

          -  Patients having out of range values for:

        Absolute neutrophil count (ANC) <1500/µL; Platelets < 100 000/µL

        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:5.5 years
Safety Issue:
Description:During the first two cycles Cycle = 28 days

Secondary Outcome Measures

Measure:Quantification of Tumor Infiltrating Lymphocytes (TILs) by Hematoxylin
Time Frame:6 years
Safety Issue:
Description:Baseline and approximately after 2 cycles of treatment and at disease progression (an average of 6 months) Cycle = 28 days
Measure:Changes from baseline in ECG parameters in patients recieving PDR001 in combination with Panobinostat
Time Frame:6 years
Safety Issue:
Description:Baseline and end of treatment, an average of 6 months
Measure:Best overall response (BOR)
Time Frame:6 years
Safety Issue:
Description:per RECIST v1.1
Measure:Time to reach max concentration (Tmax) for PDR001
Time Frame:6 years
Safety Issue:
Description:
Measure:Presence of anti-PDR001 antibodies
Time Frame:6 years
Safety Issue:
Description:
Measure:Progression free survival (PFS)
Time Frame:6 years
Safety Issue:
Description:per RECIST v1.1
Measure:Treatment Free Survival (TFS)
Time Frame:6 years
Safety Issue:
Description:
Measure:Maximum and minimum plasma concentrations of LCL161 (Cmax and Cmin)
Time Frame:6 years
Safety Issue:
Description:Cycle 1 through cycle 6 in treatment period 1, an average of 6 months
Measure:Maximum and minimum Plasma concentrations of everolimus (Cmax and Cmin)
Time Frame:6 years
Safety Issue:
Description:Cycle 1 through cycle 6 in treatment period 1, an average of 6 months
Measure:Maximum and minimum plasma concentrations of panobinostat (Cmax and Cmin)
Time Frame:6 years
Safety Issue:
Description:Cycle 1 through cycle 6 in treatment period 1, an average of 6 months
Measure:Concentration of anti-PDR001 antibodies
Time Frame:6 years
Safety Issue:
Description:Cycle 1 through cycle 6 in treatment period 1 and 2, an average of 6 months
Measure:Characterization of TILs and myeloid cell infiltrate by IHC (such as CD8, FoxP3 and myeloid markers as appropriate)
Time Frame:6 years
Safety Issue:
Description:Baseline and approximately after 2 cycles of treatment and at disease progression (an average of 6 months)
Measure:Quantification of Tumor Infiltrating Lymphocytes (TILs) by eosin (H&E) stain
Time Frame:6 years
Safety Issue:
Description:Baseline and approximately after 2 cycles of treatment and at disease progression (an average of 6 months)
Measure:Maximum and minimum serum concentration of PDR001 (Cmax and Cmin)
Time Frame:6 years
Safety Issue:
Description:Cycle 1 through cycle 6 in treatment period 1 and 2, an average of 6 months
Measure:Area under the concentration-time curve calculated to the last concentration point (AUClast) for PDR001, as applicable
Time Frame:6 years
Safety Issue:
Description:Cycle 1 through cycle 6 in treatment period 1 and 2, an average of 6 months
Measure:Progression free survival (PFS) per irRC
Time Frame:6 years
Safety Issue:
Description:
Measure:Area under the concentration-time curve calculated to the last concentration point (AUClast) for LCL161, as applicable
Time Frame:6 years
Safety Issue:
Description:Cycle 1 through cycle 6 in treatment period 1, an average of 6 months
Measure:Time to reach max concentration (Tmax) for LCL161
Time Frame:6 years
Safety Issue:
Description:Cycle 1 through cycle 6 in treatment period 1, an average of 6 months
Measure:Time to reach max concentration (Tmax) for Everolimus
Time Frame:6 years
Safety Issue:
Description:Cycle 1 through cycle 6 in treatment period 1, an average of 6 months
Measure:Time to reach max concentration (Tmax) for Panobinostat
Time Frame:6 years
Safety Issue:
Description:Cycle 1 through cycle 6 in treatment period 1, an average of 6 months
Measure:Area under the concentration-time curve calculated to the last concentration point (AUClast) for Everolimus, as applicable
Time Frame:6 years
Safety Issue:
Description:Cycle 1 through cycle 6 in treatment period 1, an average of 6 months
Measure:Area under the concentration-time curve calculated to the last concentration point (AUClast) for Panobinostat, as applicable
Time Frame:6 years
Safety Issue:
Description:Cycle 1 through cycle 6 in treatment period 1, an average of 6 months
Measure:Maximum and minimum Plasma concentrations of QBM076 (Cmax and Cmin)
Time Frame:6 years
Safety Issue:
Description:Cycle 1 through cycle 6 in treatment period 1, an average of 6 months
Measure:Maximum and minimum Plasma concentrations of HDM201 (Cmax and Cmin)
Time Frame:6 years
Safety Issue:
Description:Cycle 1 through cycle 6 in treatment period 1, an average of 6 months
Measure:Time to reach max concentration (Tmax) for QBM076
Time Frame:6 years
Safety Issue:
Description:Cycle 1 through cycle 6 in treatment period 1, an average of 6 months
Measure:Time to reach max concentration (Tmax) for HDM201
Time Frame:6 years
Safety Issue:
Description:Cycle 1 through cycle 6 in treatment period 1, an average of 6 months
Measure:Area under the concentration-time curve calculated to the last concentration point (AUClast) for QBM076, as applicable
Time Frame:6 years
Safety Issue:
Description:Cycle 1 through cycle 6 in treatment period 1, an average of 6 months
Measure:Area under the concentration-time curve calculated to the last concentration point (AUClast) for HDM201, as applicable
Time Frame:6 years
Safety Issue:
Description:Cycle 1 through cycle 6 in treatment period 1, an average of 6 months

Details

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

Trial Keywords

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

Last Updated

August 4, 2020