A Study of PDR001 in Combination With CJM112, EGF816, Ilaris® (Canakinumab) or Mekinist® (Trametinib)

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)

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.

Study Overview

• Status: Completed
• Conditions: Colorectal Cancer, Triple Negative Breast Cancer, NSCLC - Adenocarcinoma
• Intervention / Treatment: Biological: PDR001; Biological: ACZ885; Biological: CJM112; Drug: TMT212; Drug: EGF816

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.

• Study Type: Interventional
• Enrollment (Actual): 283
• Phase: Phase 1

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium, BE-B-1200
    • Novartis Investigative Site
  • Wilrijk, Belgium, 2610
    • Novartis Investigative Site
• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • Novartis Investigative Site
  • Quebec
    • Montreal, Quebec, Canada, H3T 1E2
      • Novartis Investigative Site
• France
  • Lyon Cedex, France, 69373
    • Novartis Investigative Site
  • Paris, France, 75231
    • Novartis Investigative Site
  • Toulouse Cedex 9, France, 31059
    • Novartis Investigative Site
  • Villejuif Cedex, France, 94800
    • Novartis Investigative Site
• Israel
  • Tel Aviv, Israel, 6423906
    • Novartis Investigative Site
• Italy
  • MI
    • Milano, MI, Italy, 20132
      • Novartis Investigative Site
    • Rozzano, MI, Italy, 20089
      • Novartis Investigative Site
• Singapore
  • Singapore, Singapore, 119228
    • Novartis Investigative Site
  • Singapore, Singapore, 169610
    • Novartis Investigative Site
• Spain
  • Madrid, Spain, 28050
    • Novartis Investigative Site
  • Madrid, Spain, 28009
    • Novartis Investigative Site
  • Catalunya
    • Barcelona, Catalunya, Spain, 08036
      • Novartis Investigative Site
    • Hospitalet de LLobregat, Catalunya, Spain, 08907
      • Novartis Investigative Site
• Taiwan
  • Tainan, Taiwan, 70403
    • Novartis Investigative Site
  • Taoyuan, Taiwan, 33305
    • Novartis Investigative Site
• United States
  • Maryland
    • Baltimore, Maryland, United States, 21287-0013
      • Sidney Kimmel Comprehensive Cancer Center SC-3
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Center
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Research Institute
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas MD Anderson Cancer Center

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:

• 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.

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

23

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: PDR + ACZ 100mg Q8W	Biological: PDR001; Powder for solution for infusion; Other Names: Spartalizumab/PDR001; Biological: ACZ885; Solution for injection; Other Names: canakinumab
Experimental: PDR + ACZ 300mg Q8W	Biological: PDR001; Powder for solution for infusion; Other Names: Spartalizumab/PDR001; Biological: ACZ885; Solution for injection; Other Names: canakinumab
Experimental: PDR + ACZ RDE TNBC; PDR + ACZ Recommended Dose for Expansion (RDE) Triple Negative Breast Cancer (TNBC)	Biological: PDR001; Powder for solution for infusion; Other Names: Spartalizumab/PDR001; Biological: ACZ885; Solution for injection; Other Names: canakinumab
Experimental: PDR + ACZ RDE NSCLC; PDR + ACZ Recommended Dose for Expansion (RDE) Non-Small Cell Lung Cancer (NSCLC)	Biological: PDR001; Powder for solution for infusion; Other Names: Spartalizumab/PDR001; Biological: ACZ885; Solution for injection; Other Names: canakinumab
Experimental: PDR + ACZ RDE CRC; PDR + ACZ Recommended Dose for Expansion (RDE) Colorectal Cancer (CRC)	Biological: PDR001; Powder for solution for infusion; Other Names: Spartalizumab/PDR001; Biological: ACZ885; Solution for injection; Other Names: canakinumab
Experimental: PDR + CJM 25mg Q4W	Biological: PDR001; Powder for solution for infusion; Other Names: Spartalizumab/PDR001; Biological: CJM112; Solution for infusion
Experimental: PDR + CJM 75mg Q4W	Biological: PDR001; Powder for solution for infusion; Other Names: Spartalizumab/PDR001; Biological: CJM112; Solution for infusion
Experimental: PDR + CJM 225mg Q4W	Biological: PDR001; Powder for solution for infusion; Other Names: Spartalizumab/PDR001; Biological: CJM112; Solution for infusion
Experimental: PDR + CJM 450mg Q4W	Biological: PDR001; Powder for solution for infusion; Other Names: Spartalizumab/PDR001; Biological: CJM112; Solution for infusion
Experimental: PDR + CJM 450mg Q2W	Biological: PDR001; Powder for solution for infusion; Other Names: Spartalizumab/PDR001; Biological: CJM112; Solution for infusion
Experimental: PDR + CJM 900mg Q4W	Biological: PDR001; Powder for solution for infusion; Other Names: Spartalizumab/PDR001; Biological: CJM112; Solution for infusion
Experimental: PDR + CJM 900mg Q2W	Biological: PDR001; Powder for solution for infusion; Other Names: Spartalizumab/PDR001; Biological: CJM112; Solution for infusion
Experimental: PDR + CJM 1200mg Q4W	Biological: PDR001; Powder for solution for infusion; Other Names: Spartalizumab/PDR001; Biological: CJM112; Solution for infusion
Experimental: PDR + TMT 0.5mg QD	Biological: PDR001; Powder for solution for infusion; Other Names: Spartalizumab/PDR001; Drug: TMT212; Tablets; Other Names: trametinib
Experimental: PDR + TMT 1mg QD	Biological: PDR001; Powder for solution for infusion; Other Names: Spartalizumab/PDR001; Drug: TMT212; Tablets; Other Names: trametinib
Experimental: PDR + TMT 1mg QD, 3 Weeks on/1 Week off	Biological: PDR001; Powder for solution for infusion; Other Names: Spartalizumab/PDR001; Drug: TMT212; Tablets; Other Names: trametinib
Experimental: PDR + TMT 1.5 mg QD, 2 Weeks on/2 Weeks off	Biological: PDR001; Powder for solution for infusion; Other Names: Spartalizumab/PDR001; Drug: TMT212; Tablets; Other Names: trametinib
Experimental: PDR + TMT 1.5 mg QD, 3 Weeks on/1 Week off	Biological: PDR001; Powder for solution for infusion; Other Names: Spartalizumab/PDR001; Drug: TMT212; Tablets; Other Names: trametinib
Experimental: PDR + EGF816 25mg QD	Drug: EGF816; Tablets; Other Names: Nazartinib
Experimental: PDR + EGF816 50mg QD	Drug: EGF816; Tablets; Other Names: Nazartinib
Experimental: s.a. ACZ RDE TNBC; Single agent (s.a.) ACZ Recommended Dose for Expansion (RDE) Triple Negative Breast Cancer (TNBC)	Biological: ACZ885; Solution for injection; Other Names: canakinumab
Experimental: s.a. ACZ RDE NSCLC; Single agent (s.a.) ACZ Recommended Dose for Expansion (RDE) Non-Small Cell Lung Cancer (NSCLC)	Biological: ACZ885; Solution for injection; Other Names: canakinumab
Experimental: s.a. ACZ RDE CRC; Single agent (s.a.) ACZ Recommended Dose for Expansion (RDE) Colorectal Cancer (CRC)	Biological: ACZ885; Solution for injection; Other Names: canakinumab

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Frequency of treatment-emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) as a measure of safety	Throughout the study at every visit, an average of 1 year
Changes between baseline and post-baseline laboratory parameters and vital signs.	Baseline and throughout the study at every visit, an average of 1 year
Incidence of dose limiting toxicities (DLTs) of treatment (Escalation only)	During the first two cycles; Cycle = 28 days
Frequency of dose interruptions	Throughout the study at every visit, an average of 1 year
Dose intensities	Throughout the study at every visit, an average of 1 year
Severity of treatment-emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) as a measure of safety	Throughout the study at every visit, an average of 1 year
Frequency of dose reductions	Throughout the study at every visit, an average of 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Key secondary: Histopathology of tumor infiltrating lymphocytes (TILs)		Baseline and approximately after 2 cycles of treatment and at disease progression; Cycle = 28 days
Changes from baseline in electrocardiogram (ECG) parameters		Baseline and end of treatment, an average of 1 year
Best overall response (BOR)	T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2	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
Progression free survival (PFS) per irRC and RECIST v1.1	T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2	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
Treatment Free Survival (TFS)	T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2	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
Presence and/or concentration of anti-PDR001 antibodies.	T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2	Cycle 1 through cycle 6 in treatment period 1 and 2 (an average of 1 year)
Serum concentration of PDR001, canakinumab, CJM112	T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2	Cycle 1 through cycle 6 in treatment period 1 and 2 (an average of 1 year)
Plasma concentrations of trametinib and EGF816	T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2	Cycle 1 through cycle 6 in treatment period 1 and 2 (an average of 1 year)
Key secondary: Histopathology of myeloid cell infiltrate by IHC (such as CD8, FoxP3 and myeloid markers as appropriate).		Baseline and approximately after 3 cycles of treatment and at disease progression; cycle = 28 days
PK parameters (Eg. TMax) of EGF816	T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2	Cycle 1 through cycle 6 in treatment period 1 and 2 (an average of 1 year)
PK parameters (Eg. TMax) of trametinib	T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2	Cycle 1 through cycle 6 in treatment period 1 and 2 (an average of 1 year)
PK parameter (Eg. TMax) of PDR001	T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2	Cycle 1 through cycle 6 in treatment period 1 and 2 (an average of 1 year)
PK parameters (Eg. TMax) of canakinumab	T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2	Cycle 1 through cycle 6 in treatment period 1 and 2 (an average of 1 year)
PK parameters (Eg. TMax) of CJM112	T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2	Cycle 1 through cycle 6 in treatment period 1 and 2 (an average of 1 year)
Presence and/or concentration of anti-canakinumab antibodies.	T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2	Cycle 1 through cycle 6 in treatment period 1 and 2 (an average of 1 year)
Presence and/or concentration of anti-CJM112 antibodies.	T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2	Cycle 1 through cycle 6 in treatment period 1 and 2 (an average of 1 year)

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

• Results for CPDR001X2103 from the Novartis Clinical Trials Website

Study record dates

Study Major Dates

• Study Start (Actual): August 23, 2016
• Primary Completion (Actual): March 17, 2021
• Study Completion (Actual): March 17, 2021

Study Registration Dates

• First Submitted: May 17, 2016
• First Submitted That Met QC Criteria: September 9, 2016
• First Posted (Estimate): September 14, 2016

Study Record Updates

• Last Update Posted (Actual): March 29, 2022
• Last Update Submitted That Met QC Criteria: March 15, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: breast cancer; NSCLC; lung cancer; cancer; Colorectal cancer; Rectal cancer; Immunotherapy; Non-small cell lung cancer; colon cancer; Biomarkers; TNBC; adenocarcinoma; colon; PDR001; lung adenocarcinoma; Non small cell lung cancer; CRC; Immunomodulation; breast carcinoma; Non-small cell lung carcinoma (NSCLC); treatment of lung cancer after first metastasis; Non small cell lung carcinoma; inflammatory; Colorectal adenocarcinoma; bowel cancer; breast lump; Triple-negative breast cancer (TNBC); Large-cell lung carcinoma; Large cell lung carcinoma; Large cell lung cancer; HER2 positive metastatic breast cancer; breast cancer progression; Squamous cell lung carcinoma; estrogen-receptor (ER) positive(+) breast cancer; Bayesian logistic regression model; NSCLC (adenocarcinoma); Metastatic adenocarcinoma; cancer of the colon and rectum; large intestine; large intestine cancer; colorectum cancer; TNBC, basal type; secretory cell; adenoid cystic; medullary; ductal carcinoma; Pagets disease; breast cancer positive for human epidermal growth factor receptor 2 (HER2); Pagent's disease
• Additional Relevant MeSH Terms: Digestive System Diseases; Skin Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Breast Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Breast Neoplasms; Colorectal Neoplasms; Adenocarcinoma; Triple Negative Breast Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Immune Checkpoint Inhibitors; Trametinib; Spartalizumab; Nazartinib
• Other Study ID Numbers: CPDR001X2103; 2016-000633-49 (EudraCT Number)

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