Clinical trial NCT02890069: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Colorectal Cancer, Non-small Cell Lung Carcinoma (Adenocarcinoma), Triple Negative Breast Cancer, Renal Cell Carcinoma
Keywords: PDR001
CRC
TNBC
NSCLC
RCC
Immunomodulation
Biomarkers
Bayesian logistic regression model
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2016-09-07
Enrollment: 298
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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:

  • 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.

Primary outcomes:
measure: Phase 1: Incidence of dose limiting toxicities (DLTs)
timeFrame: 5.5 years
measure: Frequency of dose interruptions and reductions
timeFrame: 5.5 years
measure: Frequency and severity of treatment-emergent adverse events (AEs) and serious adverse events (SAEs)
timeFrame: 6 years
measure: Changes between baseline and post-baseline laboratory parameters and vital signs
timeFrame: 6 years
measure: Dose intensities
timeFrame: 6 years
Secondary outcomes:
measure: Changes from baseline in ECG parameters in patients recieving PDR001 in combination with Panobinostat
timeFrame: 6 years
measure: Best overall response (BOR)
timeFrame: 6 years
measure: Time to reach max concentration (Tmax) for PDR001
timeFrame: 6 years
measure: Presence of anti-PDR001 antibodies
timeFrame: 6 years
measure: Progression free survival (PFS)
timeFrame: 6 years
measure: Treatment Free Survival (TFS)
timeFrame: 6 years
measure: Maximum and minimum plasma concentrations of LCL161 (Cmax and Cmin)
timeFrame: 6 years
measure: Maximum and minimum Plasma concentrations of everolimus (Cmax and Cmin)
timeFrame: 6 years
measure: Maximum and minimum plasma concentrations of panobinostat (Cmax and Cmin)
timeFrame: 6 years
measure: Concentration of anti-PDR001 antibodies
timeFrame: 6 years
measure: Maximum and minimum serum concentration of PDR001 (Cmax and Cmin)
timeFrame: 6 years
measure: Area under the concentration-time curve calculated to the last concentration point (AUClast) for PDR001, as applicable
timeFrame: 6 years
measure: Progression free survival (PFS) per irRC
timeFrame: 6 years
measure: Area under the concentration-time curve calculated to the last concentration point (AUClast) for LCL161, as applicable
timeFrame: 6 years
measure: Time to reach max concentration (Tmax) for LCL161
timeFrame: 6 years
measure: Time to reach max concentration (Tmax) for Everolimus
timeFrame: 6 years
measure: Time to reach max concentration (Tmax) for Panobinostat
timeFrame: 6 years
measure: Area under the concentration-time curve calculated to the last concentration point (AUClast) for Everolimus, as applicable
timeFrame: 6 years
measure: Area under the concentration-time curve calculated to the last concentration point (AUClast) for Panobinostat, as applicable
timeFrame: 6 years
measure: Maximum and minimum Plasma concentrations of QBM076 (Cmax and Cmin)
timeFrame: 6 years
measure: Maximum and minimum Plasma concentrations of HDM201 (Cmax and Cmin)
timeFrame: 6 years
measure: Time to reach max concentration (Tmax) for QBM076
timeFrame: 6 years
measure: Time to reach max concentration (Tmax) for HDM201
timeFrame: 6 years
measure: Area under the concentration-time curve calculated to the last concentration point (AUClast) for QBM076, as applicable
timeFrame: 6 years
measure: Area under the concentration-time curve calculated to the last concentration point (AUClast) for HDM201, as applicable
timeFrame: 6 years
Other outcomes:
Locations:
city: Santa Monica
country: United States
facility: UCLA Santa Monica Hematology / Oncology SC
state: California
city: Baltimore
country: United States
facility: Sidney Kimmel Comprehensive Cancer Center
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Ann Arbor
country: United States
facility: The Regents of the University of Michigan
state: Michigan
city: Saint Louis
country: United States
facility: Washington University Medical School SC
state: Missouri
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center
state: Texas
city: San Antonio
country: United States
facility: UT Health San Antonio Mays Cancer Center
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute
state: Utah
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance
state: Washington
city: Jena
country: Germany
facility: Novartis Investigative Site
city: Ulm
country: Germany
facility: Novartis Investigative Site
city: Wuerzburg
country: Germany
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
state: Korea
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Amsterdam
country: Netherlands
facility: Novartis Investigative Site
city: Leiden
country: Netherlands
facility: Novartis Investigative Site
city: Rotterdam
country: Netherlands
facility: Novartis Investigative Site
city: Utrecht
country: Netherlands
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Pamplona
country: Spain
facility: Novartis Investigative Site
state: Navarra
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Sutton
country: United Kingdom
facility: Novartis Investigative Site
state: Surrey
city: Manchester
country: United Kingdom
facility: Novartis Investigative Site
city: Oxford
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: