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

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)

The purpose of this study was 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.

Study Overview

• Status: Completed
• Conditions: Colorectal Cancer, Non-small Cell Lung Carcinoma (Adenocarcinoma), Triple Negative Breast Cancer, Renal Cell Carcinoma
• Intervention / Treatment: Drug: Everolimus; Drug: Panobinostat; Biological: PDR001; Drug: LCL161; Drug: QBM076; Drug: HDM201

• Study Type: Interventional
• Enrollment (Actual): 298
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Jena, Germany, 07740
    • Novartis Investigative Site
  • Ulm, Germany, 89081
    • Novartis Investigative Site
  • Wuerzburg, Germany, 97080
    • Novartis Investigative Site
• Korea, Republic of
  • Seoul, Korea, Republic of, 03080
    • Novartis Investigative Site
  • Korea
    • Seoul, Korea, Korea, Republic of, 05505
      • Novartis Investigative Site
• Netherlands
  • Amsterdam, Netherlands, 1066 CX
    • Novartis Investigative Site
  • Leiden, Netherlands, 2300 RC
    • Novartis Investigative Site
  • Rotterdam, Netherlands, 3075 EA
    • Novartis Investigative Site
  • Utrecht, Netherlands, 3584CX
    • Novartis Investigative Site
• Spain
  • Madrid, Spain, 28041
    • Novartis Investigative Site
  • Catalunya
    • Barcelona, Catalunya, Spain, 08035
      • Novartis Investigative Site
  • Navarra
    • Pamplona, Navarra, Spain, 31008
      • Novartis Investigative Site
• Taiwan
  • Taipei, Taiwan, 10002
    • Novartis Investigative Site
• United Kingdom
  • Manchester, United Kingdom, M20 4BX
    • Novartis Investigative Site
  • Oxford, United Kingdom, OX3 7LJ
    • Novartis Investigative Site
  • Surrey
    • Sutton, Surrey, United Kingdom, SM2 5PT
      • Novartis Investigative Site
• United States
  • California
    • Santa Monica, California, United States, 90404
      • UCLA Santa Monica Hematology / Oncology SC
  • Maryland
    • Baltimore, Maryland, United States, 21231
      • Sidney Kimmel Comprehensive Cancer Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • The Regents of the University of Michigan
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University Medical School SC
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas MD Anderson Cancer Center
    • San Antonio, Texas, United States, 78229
      • UT Health San Antonio Mays Cancer Center
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Huntsman Cancer Institute
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Cancer Care Alliance

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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:

  • CRC •NSCLC • 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

14

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CRC - PDR001 + LCL161; Enrollment to this combination arm is closed to further enrollment.	Biological: PDR001; anti-PD1 antibody; Drug: LCL161
Experimental: NSCLC - PDR001 + LCL161; Enrollment to this combination arm is closed to further enrollment.	Biological: PDR001; anti-PD1 antibody; Drug: LCL161
Experimental: TNBC - PDR001 + LCL161; Enrollment to this combination arm is closed to further enrollment.	Biological: PDR001; anti-PD1 antibody; Drug: LCL161
Experimental: CRC - PDR001+ Everolimus; Enrollment to this combination arm is closed to further enrollment.	Drug: Everolimus; Other Names: RAD001; Biological: PDR001; anti-PD1 antibody
Experimental: NSCLC - PDR001+ Everolimus; Enrollment to this combination arm is closed to further enrollment.	Drug: Everolimus; Other Names: RAD001; Biological: PDR001; anti-PD1 antibody
Experimental: TNBC - PDR001+ Everolimus; Enrollment to this combination arm is closed to further enrollment.	Drug: Everolimus; Other Names: RAD001; Biological: PDR001; anti-PD1 antibody
Experimental: CRC - PDR001 + Panobinostat; Enrollment to this combination arm is closed to further enrollment.	Drug: Panobinostat; Other Names: LBH589; Biological: PDR001; anti-PD1 antibody
Experimental: NSCLC - PDR001 + Panobinostat; Enrollment to this combination arm is closed to further enrollment.	Drug: Panobinostat; Other Names: LBH589; Biological: PDR001; anti-PD1 antibody
Experimental: TNBC - PDR001 + Panobinostat; Enrollment to this combination arm is closed to further enrollment.	Drug: Panobinostat; Other Names: LBH589; Biological: PDR001; anti-PD1 antibody
Experimental: CRC - PDR001 + QBM076; Enrollment to this combination arm is closed to further enrollment.	Drug: QBM076
Experimental: TNBC - PDR001 + QBM076; Enrollment to this combination arm is closed to further enrollment.	Drug: QBM076
Experimental: NSCLC- PDR001 + QBM076; Enrollment to this combination arm is closed to further enrollment.	Drug: QBM076
Experimental: CRC - PDR001 + HDM201; Dose escalation completed, expansion arm.	Drug: HDM201
Experimental: RCC - PDR001 + HDM201; Dose escalation completed, expansion arm.	Drug: HDM201

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1: Incidence of dose limiting toxicities (DLTs)	During the first two cycles Cycle = 28 days	5.5 years
Frequency of dose interruptions and reductions	Through study completion, an average of 6 months	5.5 years
Frequency and severity of treatment-emergent adverse events (AEs) and serious adverse events (SAEs)	Through study completion, an average of 6 months	6 years
Changes between baseline and post-baseline laboratory parameters and vital signs	Through study completion, an average of 6 months	6 years
Dose intensities	Through study completion, an average of 6 months	6 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes from baseline in ECG parameters in patients recieving PDR001 in combination with Panobinostat	Baseline and end of treatment, an average of 6 months	6 years
Best overall response (BOR)	per RECIST v1.1	6 years
Time to reach max concentration (Tmax) for PDR001		6 years
Presence of anti-PDR001 antibodies		6 years
Progression free survival (PFS)	per RECIST v1.1	6 years
Treatment Free Survival (TFS)		6 years
Maximum and minimum plasma concentrations of LCL161 (Cmax and Cmin)	Cycle 1 through cycle 6 in treatment period 1, an average of 6 months	6 years
Maximum and minimum Plasma concentrations of everolimus (Cmax and Cmin)	Cycle 1 through cycle 6 in treatment period 1, an average of 6 months	6 years
Maximum and minimum plasma concentrations of panobinostat (Cmax and Cmin)	Cycle 1 through cycle 6 in treatment period 1, an average of 6 months	6 years
Concentration of anti-PDR001 antibodies	Cycle 1 through cycle 6 in treatment period 1 and 2, an average of 6 months	6 years
Maximum and minimum serum concentration of PDR001 (Cmax and Cmin)	Cycle 1 through cycle 6 in treatment period 1 and 2, an average of 6 months	6 years
Area under the concentration-time curve calculated to the last concentration point (AUClast) for PDR001, as applicable	Cycle 1 through cycle 6 in treatment period 1 and 2, an average of 6 months	6 years
Progression free survival (PFS) per irRC		6 years
Area under the concentration-time curve calculated to the last concentration point (AUClast) for LCL161, as applicable	Cycle 1 through cycle 6 in treatment period 1, an average of 6 months	6 years
Time to reach max concentration (Tmax) for LCL161	Cycle 1 through cycle 6 in treatment period 1, an average of 6 months	6 years
Time to reach max concentration (Tmax) for Everolimus	Cycle 1 through cycle 6 in treatment period 1, an average of 6 months	6 years
Time to reach max concentration (Tmax) for Panobinostat	Cycle 1 through cycle 6 in treatment period 1, an average of 6 months	6 years
Area under the concentration-time curve calculated to the last concentration point (AUClast) for Everolimus, as applicable	Cycle 1 through cycle 6 in treatment period 1, an average of 6 months	6 years
Area under the concentration-time curve calculated to the last concentration point (AUClast) for Panobinostat, as applicable	Cycle 1 through cycle 6 in treatment period 1, an average of 6 months	6 years
Maximum and minimum Plasma concentrations of QBM076 (Cmax and Cmin)	Cycle 1 through cycle 6 in treatment period 1, an average of 6 months	6 years
Maximum and minimum Plasma concentrations of HDM201 (Cmax and Cmin)	Cycle 1 through cycle 6 in treatment period 1, an average of 6 months	6 years
Time to reach max concentration (Tmax) for QBM076	Cycle 1 through cycle 6 in treatment period 1, an average of 6 months	6 years
Time to reach max concentration (Tmax) for HDM201	Cycle 1 through cycle 6 in treatment period 1, an average of 6 months	6 years
Area under the concentration-time curve calculated to the last concentration point (AUClast) for QBM076, as applicable	Cycle 1 through cycle 6 in treatment period 1, an average of 6 months	6 years
Area under the concentration-time curve calculated to the last concentration point (AUClast) for HDM201, as applicable	Cycle 1 through cycle 6 in treatment period 1, an average of 6 months	6 years

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

• Study Results

Study record dates

Study Major Dates

• Study Start (Actual): October 14, 2016
• Primary Completion (Actual): February 22, 2022
• Study Completion (Actual): February 22, 2022

Study Registration Dates

• First Submitted: May 9, 2016
• First Submitted That Met QC Criteria: August 31, 2016
• First Posted (Estimate): September 7, 2016

Study Record Updates

• Last Update Posted (Estimate): January 11, 2023
• Last Update Submitted That Met QC Criteria: January 10, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: NSCLC; Biomarkers; TNBC; PDR001; CRC; Immunomodulation; RCC; Bayesian logistic regression model
• Additional Relevant MeSH Terms: Skin Diseases; Respiratory Tract Diseases; Neoplasms by Histologic Type; Neoplasms; Lung Diseases; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Breast Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Breast Neoplasms; Kidney Neoplasms; Carcinoma, Renal Cell; Carcinoma, Non-Small-Cell Lung; Triple Negative Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Immune Checkpoint Inhibitors; Histone Deacetylase Inhibitors; Everolimus; Spartalizumab; Panobinostat
• Other Study ID Numbers: CPDR001X2102

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No