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

• ClinicalTrials.gov Identifier: NCT02890069
• Recruitment Status: Completed
• First Posted: September 7, 2016
• Last Update Posted: January 11, 2023
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Colorectal Cancer, Non-small Cell Lung Carcinoma (Adenocarcinoma), Triple Negative Breast Cancer, Renal Cell Carcinoma	Biological: PDR001; Drug: LCL161; Drug: Everolimus; Drug: Panobinostat; Drug: QBM076; Drug: HDM201	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 298 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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)
• Actual Study Start Date: October 14, 2016
• Actual Primary Completion Date: February 22, 2022
• Actual Study Completion Date: February 22, 2022

Arms and Interventions

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.	Biological: PDR001; anti-PD1 antibody; Drug: Everolimus; Other Name: RAD001
Experimental: NSCLC - PDR001+ Everolimus; Enrollment to this combination arm is closed to further enrollment.	Biological: PDR001; anti-PD1 antibody; Drug: Everolimus; Other Name: RAD001
Experimental: TNBC - PDR001+ Everolimus; Enrollment to this combination arm is closed to further enrollment.	Biological: PDR001; anti-PD1 antibody; Drug: Everolimus; Other Name: RAD001
Experimental: CRC - PDR001 + Panobinostat; Enrollment to this combination arm is closed to further enrollment.	Biological: PDR001; anti-PD1 antibody; Drug: Panobinostat; Other Name: LBH589
Experimental: NSCLC - PDR001 + Panobinostat; Enrollment to this combination arm is closed to further enrollment.	Biological: PDR001; anti-PD1 antibody; Drug: Panobinostat; Other Name: LBH589
Experimental: TNBC - PDR001 + Panobinostat; Enrollment to this combination arm is closed to further enrollment.	Biological: PDR001; anti-PD1 antibody; Drug: Panobinostat; Other Name: LBH589
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

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

1. Changes from baseline in ECG parameters in patients recieving PDR001 in combination with Panobinostat [ Time Frame: 6 years ]
   Baseline and end of treatment, an average of 6 months
2. Best overall response (BOR) [ Time Frame: 6 years ]
   per RECIST v1.1
3. Time to reach max concentration (Tmax) for PDR001 [ Time Frame: 6 years ]
4. Presence of anti-PDR001 antibodies [ Time Frame: 6 years ]
5. Progression free survival (PFS) [ Time Frame: 6 years ]
   per RECIST v1.1
6. Treatment Free Survival (TFS) [ Time Frame: 6 years ]
7. Maximum and minimum plasma concentrations of LCL161 (Cmax and Cmin) [ Time Frame: 6 years ]
   Cycle 1 through cycle 6 in treatment period 1, an average of 6 months
8. Maximum and minimum Plasma concentrations of everolimus (Cmax and Cmin) [ Time Frame: 6 years ]
   Cycle 1 through cycle 6 in treatment period 1, an average of 6 months
9. Maximum and minimum plasma concentrations of panobinostat (Cmax and Cmin) [ Time Frame: 6 years ]
   Cycle 1 through cycle 6 in treatment period 1, an average of 6 months
10. Concentration of anti-PDR001 antibodies [ Time Frame: 6 years ]
    Cycle 1 through cycle 6 in treatment period 1 and 2, an average of 6 months
11. Maximum and minimum serum concentration of PDR001 (Cmax and Cmin) [ Time Frame: 6 years ]
    Cycle 1 through cycle 6 in treatment period 1 and 2, an average of 6 months
12. Area under the concentration-time curve calculated to the last concentration point (AUClast) for PDR001, as applicable [ Time Frame: 6 years ]
    Cycle 1 through cycle 6 in treatment period 1 and 2, an average of 6 months
13. Progression free survival (PFS) per irRC [ Time Frame: 6 years ]
14. Area under the concentration-time curve calculated to the last concentration point (AUClast) for LCL161, as applicable [ Time Frame: 6 years ]
    Cycle 1 through cycle 6 in treatment period 1, an average of 6 months
15. Time to reach max concentration (Tmax) for LCL161 [ Time Frame: 6 years ]
    Cycle 1 through cycle 6 in treatment period 1, an average of 6 months
16. Time to reach max concentration (Tmax) for Everolimus [ Time Frame: 6 years ]
    Cycle 1 through cycle 6 in treatment period 1, an average of 6 months
17. Time to reach max concentration (Tmax) for Panobinostat [ Time Frame: 6 years ]
    Cycle 1 through cycle 6 in treatment period 1, an average of 6 months
18. Area under the concentration-time curve calculated to the last concentration point (AUClast) for Everolimus, as applicable [ Time Frame: 6 years ]
    Cycle 1 through cycle 6 in treatment period 1, an average of 6 months
19. Area under the concentration-time curve calculated to the last concentration point (AUClast) for Panobinostat, as applicable [ Time Frame: 6 years ]
    Cycle 1 through cycle 6 in treatment period 1, an average of 6 months
20. Maximum and minimum Plasma concentrations of QBM076 (Cmax and Cmin) [ Time Frame: 6 years ]
    Cycle 1 through cycle 6 in treatment period 1, an average of 6 months
21. Maximum and minimum Plasma concentrations of HDM201 (Cmax and Cmin) [ Time Frame: 6 years ]
    Cycle 1 through cycle 6 in treatment period 1, an average of 6 months
22. Time to reach max concentration (Tmax) for QBM076 [ Time Frame: 6 years ]
    Cycle 1 through cycle 6 in treatment period 1, an average of 6 months
23. Time to reach max concentration (Tmax) for HDM201 [ Time Frame: 6 years ]
    Cycle 1 through cycle 6 in treatment period 1, an average of 6 months
24. Area under the concentration-time curve calculated to the last concentration point (AUClast) for QBM076, as applicable [ Time Frame: 6 years ]
    Cycle 1 through cycle 6 in treatment period 1, an average of 6 months
25. Area under the concentration-time curve calculated to the last concentration point (AUClast) for HDM201, as applicable [ Time Frame: 6 years ]
    Cycle 1 through cycle 6 in treatment period 1, an average of 6 months

Eligibility Criteria

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

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:

  • 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.

Contacts and Locations

Locations

United States, California

UCLA Santa Monica Hematology / Oncology SC

Santa Monica, California, United States, 90404

United States, Maryland

Sidney Kimmel Comprehensive Cancer Center

Baltimore, Maryland, United States, 21231

United States, Massachusetts

Massachusetts General Hospital

Boston, Massachusetts, United States, 02114

United States, Michigan

The Regents of the University of Michigan

Ann Arbor, Michigan, United States, 48109

United States, Missouri

Washington University Medical School SC

Saint Louis, Missouri, United States, 63110

United States, Texas

University of Texas MD Anderson Cancer Center

Houston, Texas, United States, 77030

UT Health San Antonio Mays Cancer Center

San Antonio, Texas, United States, 78229

United States, Utah

Huntsman Cancer Institute

Salt Lake City, Utah, United States, 84112

United States, Washington

Seattle Cancer Care Alliance

Seattle, Washington, United States, 98105

Germany

Novartis Investigative Site

Jena, Germany, 07740

Novartis Investigative Site

Ulm, Germany, 89081

Novartis Investigative Site

Wuerzburg, Germany, 97080

Korea, Republic of

Novartis Investigative Site

Seoul, Korea, Korea, Republic of, 05505

Novartis Investigative Site

Seoul, Korea, Republic of, 03080

Netherlands

Novartis Investigative Site

Amsterdam, Netherlands, 1066 CX

Novartis Investigative Site

Leiden, Netherlands, 2300 RC

Novartis Investigative Site

Rotterdam, Netherlands, 3075 EA

Novartis Investigative Site

Utrecht, Netherlands, 3584CX

Spain

Novartis Investigative Site

Barcelona, Catalunya, Spain, 08035

Novartis Investigative Site

Pamplona, Navarra, Spain, 31008

Novartis Investigative Site

Madrid, Spain, 28041

Taiwan

Novartis Investigative Site

Taipei, Taiwan, 10002

United Kingdom

Novartis Investigative Site

Sutton, Surrey, United Kingdom, SM2 5PT

Novartis Investigative Site

Manchester, United Kingdom, M20 4BX

Novartis Investigative Site

Oxford, United Kingdom, OX3 7LJ

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

More Information

Additional Information:

Study Results 

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02890069
• Other Study ID Numbers: CPDR001X2102
• First Posted: September 7, 2016
• Last Update Posted: January 11, 2023
• Last Verified: January 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):

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

Additional relevant MeSH terms:

Carcinoma, Renal Cell; Triple Negative Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Kidney Neoplasms; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Urologic Neoplasms; Urogenital Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases; Breast Neoplasms; Breast Diseases; Skin Diseases; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Everolimus; Panobinostat