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

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Completed

CT.gov ID

NCT02890069

Collaborator

(none)

298

Enrollment

Locations

Arms

64.3

Actual Duration (Months)

11.9

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

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

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 :

Oct 14, 2016

Actual Primary Completion Date :

Feb 22, 2022

Actual Study Completion Date :

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

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

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

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