Colorectal Cancer, Triple Negative Breast Cancer, NSCLC - Adenocarcinoma
Conditions
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
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.
Interventions
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| 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 |
| 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 |
| 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Serum concentration of PDR001, canakinumab, CJM112 | Cycle 1 through cycle 6 in treatment period 1 and 2 (an average of 1 year) | T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2 |
| 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 | Cycle 1 through cycle 6 in treatment period 1 and 2 (an average of 1 year) | T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2 |
| PK parameters (Eg. TMax) of trametinib | Cycle 1 through cycle 6 in treatment period 1 and 2 (an average of 1 year) | T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2 |
| Key secondary: Histopathology of tumor infiltrating lymphocytes (TILs) | Baseline and approximately after 2 cycles of treatment and at disease progression; Cycle = 28 days | — |
| PK parameters (Eg. TMax) of canakinumab | Cycle 1 through cycle 6 in treatment period 1 and 2 (an average of 1 year) | T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2 |
| PK parameters (Eg. TMax) of CJM112 | Cycle 1 through cycle 6 in treatment period 1 and 2 (an average of 1 year) | T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2 |
| Presence and/or concentration of anti-canakinumab antibodies. | Cycle 1 through cycle 6 in treatment period 1 and 2 (an average of 1 year) | T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2 |
| Presence and/or concentration of anti-CJM112 antibodies. | Cycle 1 through cycle 6 in treatment period 1 and 2 (an average of 1 year) | T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2 |
| PK parameter (Eg. TMax) of PDR001 | Cycle 1 through cycle 6 in treatment period 1 and 2 (an average of 1 year) | T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2 |
| Changes from baseline in electrocardiogram (ECG) parameters | Baseline and end of treatment, an average of 1 year | — |
| Best overall response (BOR) | 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 | T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2 |
| Progression free survival (PFS) per irRC and RECIST v1.1 | 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 | T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2 |
| Plasma concentrations of trametinib and EGF816 | Cycle 1 through cycle 6 in treatment period 1 and 2 (an average of 1 year) | T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2 |
| Treatment Free Survival (TFS) | 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 | T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2 |
| Presence and/or concentration of anti-PDR001 antibodies. | Cycle 1 through cycle 6 in treatment period 1 and 2 (an average of 1 year) | T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2 |
Countries
Belgium, Canada, France, Israel, Italy, Singapore, Spain, Taiwan, United States
Outcome results
None listed