Clinical trial NCT02900664: A Study of PDR001 in Combination With CJM112, EGF816, Ilaris® (Canakinumab) or Mekinist® (Trametinib)
Official title: Phase Ib, Open-label, Multi-center Study to Characterize the Safety, Tolerability and Pharmacodynamics (PD) of PDR001 in Combination With CJM112, EGF816, Ilaris® (Canakinumab) or Mekinist® (Trametinib)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Colorectal Cancer, Triple Negative Breast Cancer, NSCLC - Adenocarcinoma
Keywords: CRC
TNBC
NSCLC (adenocarcinoma)
Immunomodulation
Biomarkers
Bayesian logistic regression model
PDR001
Immunotherapy
Rectal cancer
Metastatic adenocarcinoma
Colorectal cancer
colon cancer
bowel cancer
cancer of the colon and rectum
Colorectal adenocarcinoma
adenocarcinoma
colon
cancer
large intestine
large intestine cancer
colorectum cancer
Triple-negative breast cancer (TNBC)
TNBC, basal type
secretory cell
adenoid cystic
medullary
ductal carcinoma
inflammatory
breast carcinoma
breast cancer
breast lump
Pagets disease
HER2 positive metastatic breast cancer
breast cancer positive for human epidermal growth factor receptor 2 (HER2)
breast cancer progression
estrogen-receptor (ER) positive(+) breast cancer
Non-small cell lung carcinoma (NSCLC)
treatment of lung cancer after first metastasis
lung cancer
lung adenocarcinoma
Squamous cell lung carcinoma
Large-cell lung carcinoma
Non small cell lung carcinoma
Non small cell lung cancer
Non-small cell lung cancer
NSCLC
Large cell lung carcinoma
Large cell lung cancer
Pagent's disease
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2016-09-14
Enrollment: 283
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 each of four 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.

Detailed description: This was a Phase Ib, multi-center, open-label study, to characterize the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activity of PDR001 in combination with canakinumab, CJM112, trametinib and EGF816 and single agent (s.a.) canakinumab in subjects with Triple Negative Breast Cancer (TNBC), Non-Small Cell Lung Cancer (NSCLC) and Colorectal Cancer (CRC). The study comprised a dose escalation part for combination treatments only, followed by a dose expansion part.

Eligibility criteria: Inclusion Criteria:

* 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 standard therapy, and for whom no effective therapy is available.

Patients must fit into one of the following groups:

* Colorectal cancer (CRC) (not mismatch repair deficient by local assay including PCR and/or immunohistochemistry)
* Non-small cell lung cancer (NSCLC) (adenocarcinoma)
* Triple Negative Breast Cancer (TNBC) (D
* ECOG Performance Status ≤ 2
* Patient must have a site of disease amenable to biopsy, and be a candidate for tumor biopsy according to the treating institution's guidelines. Patient must be willing to undergo a new tumor biopsy at baseline, 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.
* Written informed consent must be obtained prior to any screening procedures other than procedures performed as part of standard of care.

Exclusion Criteria:

* Presence of symptomatic central nervous system (CNS) metastases, or CNS metastases that require local CNS-directed therapy, or increasing doses of corticosteroids within the prior 2 weeks.
* History of severe hypersensitivity reactions to other monoclonal antibodies.
* Out of range laboratory values for measures of hepatic and renal function, electrolytes and blood counts
* Impaired cardiac function or clinically significant cardiac disease.
* Patients with active, known or suspected autoimmune disease.
* Human Immunodeficiency Virus infection at screening.
* Escalation part: Active Hepatitis B (HBV) or Hepatitis C (HCV) virus infection at screening.

Expansion part: Patients with active HBV or HCV are excluded, excepting those patients undergoing treatment for HBV or HCV.

* Malignant disease, other than that being treated in this study.
* Recent systemic anti-cancer therapy
* Active infection requiring systemic antibiotic therapy.
* Patients requiring chronic treatment with systemic steroid therapy, other than replacement dose steroids in the setting of adrenal insufficiency or treatment with low, stable dose of steroid (\<10mg/ day prednisone or equivalent) for stable CNS metastatic disease.
* Patients receiving systemic treatment with any immunosuppressive medication, excepting the above
* Use of any live vaccines against infectious diseases (e.g. influenza, varicella, pneumococcus) within 4 weeks of initiation of study treatment.
* Participation in an interventional, investigational study within 2 weeks of the first dose of study treatment.
* Presence of ≥ CTCAE grade 2 toxicity (except alopecia and ototoxicity, which are excluded if ≥ CTCAE grade 3) due to prior cancer therapy.
* Recent use of hematopoietic colony-stimulating growth factors (e.g. G-CSF, GMCSF, M-CSF)

Additional exclusion criteria for Combination arm PDR001+canakinumab and single-agent canakinumab

* Patients with tuberculosis (TB). Note: Patient with latent TB may be eligible based on the investigator's benefit-risk assessment.
* Patients who have been infected with HBV or HCV including those with inactive disease.

Additional exclusion criteria for Combination arm PDR001+CJM112

* Patients with TB. Note: Patient with latent TB may be eligible based on the investigator's benefit-risk assessment.
* Patients with history of and/or active inflammatory bowel disease.
* Active skin or soft tissue infection including cellulitis, erysipelas, impetigo, furuncle,carbuncle, abscess, or fasciitis.
* Active candida infection, including mucocutaneous infection or history of invasive candidiasis.

Additional exclusion criteria for Combination arm PDR001+trametinib

* Patients with history of retinal vein oclusion.
* Patients with history of interstitial lung disease or pneumonitis.
* Patients with cardiomyopathy and/or LVEF \< LLN.
* Impairment of gastrointestinal function or GI disease that may significantly alter the absorption of oral combination partners.
* Hemoglobin (Hgb) \< 9 g/dL without growth factor or transfusion support
* Women of child-bearing potential using hormonal contraception, unless an additional contraception method is also used according to the Mekinist® label.

Additional exclusion criteria for Combination arm PDR001+EGF816

* NSCLC patients with EGFR mutant tumors.
* Strong inhibitors and strong inducers of CYP3A4 should not be used concomitantly.
* Patients with history of interstitial lung disease.
* Patients who have been infected with HBV or HCV including those with inactive disease.
* Impairment of gastrointestinal function or GI disease that may significantly alter the absorption of oral combination partners
* Patients cannot have received radiotherapy to lung fields within 6 months of study treatment start.

Primary outcomes:
measure: Frequency of treatment-emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) as a measure of safety
timeFrame: Throughout the study at every visit, an average of 1 year
measure: Changes between baseline and post-baseline laboratory parameters and vital signs.
timeFrame: Baseline and throughout the study at every visit, an average of 1 year
measure: Incidence of dose limiting toxicities (DLTs) of treatment (Escalation only)
timeFrame: During the first two cycles; Cycle = 28 days
measure: Frequency of dose interruptions
timeFrame: Throughout the study at every visit, an average of 1 year
measure: Dose intensities
timeFrame: Throughout the study at every visit, an average of 1 year
measure: Severity of treatment-emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) as a measure of safety
timeFrame: Throughout the study at every visit, an average of 1 year
measure: Frequency of dose reductions
timeFrame: Throughout the study at every visit, an average of 1 year
Secondary outcomes:
measure: Key secondary: Histopathology of tumor infiltrating lymphocytes (TILs)
timeFrame: Baseline and approximately after 2 cycles of treatment and at disease progression; Cycle = 28 days
measure: Changes from baseline in electrocardiogram (ECG) parameters
timeFrame: Baseline and end of treatment, an average of 1 year
measure: Best overall response (BOR)
timeFrame: T1: Every 2 cycles until the start of T2. T2: Every 2 cycles until cycle 3 and then every 3 cycles until PD; cycle = 28 days
measure: Progression free survival (PFS) per irRC and RECIST v1.1
timeFrame: T1: Every 2 cycles until the start of T2. T2: Every 2 cycles until cycle 3 and then every 3 cycles until PD; cycle = 28 days
measure: Treatment Free Survival (TFS)
timeFrame: T1: Every 2 cycles until the start of T2. T2: Every 2 cycles until cycle 3 and then every 3 cycles until PD; cycle = 28 days
measure: Presence and/or concentration of anti-PDR001 antibodies.
timeFrame: Cycle 1 through cycle 6 in treatment period 1 and 2 (an average of 1 year)
measure: Serum concentration of PDR001, canakinumab, CJM112
timeFrame: Cycle 1 through cycle 6 in treatment period 1 and 2 (an average of 1 year)
measure: Plasma concentrations of trametinib and EGF816
timeFrame: Cycle 1 through cycle 6 in treatment period 1 and 2 (an average of 1 year)
measure: Key secondary: Histopathology of myeloid cell infiltrate by IHC (such as CD8, FoxP3 and myeloid markers as appropriate).
timeFrame: Baseline and approximately after 3 cycles of treatment and at disease progression; cycle = 28 days
measure: PK parameters (Eg. TMax) of EGF816
timeFrame: Cycle 1 through cycle 6 in treatment period 1 and 2 (an average of 1 year)
measure: PK parameters (Eg. TMax) of trametinib
timeFrame: Cycle 1 through cycle 6 in treatment period 1 and 2 (an average of 1 year)
measure: PK parameter (Eg. TMax) of PDR001
timeFrame: Cycle 1 through cycle 6 in treatment period 1 and 2 (an average of 1 year)
measure: PK parameters (Eg. TMax) of canakinumab
timeFrame: Cycle 1 through cycle 6 in treatment period 1 and 2 (an average of 1 year)
measure: PK parameters (Eg. TMax) of CJM112
timeFrame: Cycle 1 through cycle 6 in treatment period 1 and 2 (an average of 1 year)
measure: Presence and/or concentration of anti-canakinumab antibodies.
timeFrame: Cycle 1 through cycle 6 in treatment period 1 and 2 (an average of 1 year)
measure: Presence and/or concentration of anti-CJM112 antibodies.
timeFrame: Cycle 1 through cycle 6 in treatment period 1 and 2 (an average of 1 year)
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: Sidney Kimmel Comprehensive Cancer Center SC-3
state: Maryland
city: Boston
country: United States
facility: Dana Farber Cancer Center
state: Massachusetts
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center
state: Texas
city: Brussels
country: Belgium
facility: Novartis Investigative Site
city: Wilrijk
country: Belgium
facility: Novartis Investigative Site
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Montreal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Lyon Cedex
country: France
facility: Novartis Investigative Site
city: Paris
country: France
facility: Novartis Investigative Site
city: Toulouse Cedex 9
country: France
facility: Novartis Investigative Site
city: Villejuif Cedex
country: France
facility: Novartis Investigative Site
city: Tel Aviv
country: Israel
facility: Novartis Investigative Site
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Rozzano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Hospitalet de LLobregat
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Tainan
country: Taiwan
facility: Novartis Investigative Site
city: Taoyuan
country: Taiwan
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: