Adrenocortical Carcinoma (Part G), Advanced Solid Tumors (Part A/B/C/D), High-circulating Myeloid-derived Suppressor Cells (Part H), Melanoma (Part E), Mesothelioma (Part G), Non-small Cell Lung Cancer (Part E), Squamous Cell Cancer of the Head and Neck (Part E), Triple Negative Breast Cancer (Part F)
Conditions
Keywords
IPI-549, Phase 1, Advanced Solid Tumor, Non-small cell lung cancer, Melanoma, PI3K, Squamous Cell Cancer of the Head and Neck, Triple Negative Breast Cancer, Adrenocortical Carcinoma, Mesothelioma, High-circulating myeloid-derived suppressor cells (MDSCs), eganelisib
Brief summary
This dose-escalation study will evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of IPI-549 monotherapy and IPI-549 in combination with nivolumab in subjects with advanced solid tumors.
Detailed description
Study IPI-549-01 is a first-in-human multicenter, open-label, up to five-part Phase 1/1b dose-escalation study designed to evaluate safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of IPI-549 monotherapy and IPI-549 in combination with nivolumab in subjects with advanced solid tumors. Approximately 175 subjects will receive IPI-549, either as a monotherapy or in combination with nivolumab. Subjects will receive IPI-549 until the maximum tolerated dose (MTD) is achieved or until disease progression or unacceptable toxicity. Part A (QD dosing) (and Part B (BID dosing) if necessary) a dose escalation part of the study will evaluate the safety and tolerability, PK, and PD of IPI-549 as a single agent in subjects with advanced solid tumors. Part A/B will determine the recommended phase 2 dose (RP2D) for IPI-549 single agent that is going to be administered in Part D as a single agent and Part C in combination with nivolumab. Part C a dose-escalation part of the study will evaluate the safety and tolerability, PK, and PD of IPI-549 when administered in combination with IV nivolumab 240 mg every 2 weeks (Q2W) in subjects with advanced solid tumors. Part C will determine the RP2D for the combination of IPI-549 and nivolumab (combination RP2D). Part D will evaluate the safety, tolerability, PK, PD, and preliminary clinical activity of IPI-549 administered as a single agent in a cohort of subjects with advanced solid tumors. Part D, Cycle 2 will also include a pilot food (a high-fat meal) effect evaluation that will have 8 subjects out of the entire cohort of subjects participating in the Part D. Part E will evaluate the safety, tolerability, PK, PD, and preliminary clinical activity of IPI-549 in combination with intravenous (IV) nivolumab 240 mg Q2W in a cohort of subjects with non-small cell lung cancer (NSCLC), a cohort of subjects with melanoma and a cohort of subjects with Squamous Cell Cancer of the Head and Neck (SCCHN). One or more cohorts of subjects with additional tumor types may be enrolled if supported by data generated in dose escalation or earlier expansion cohorts. To be eligible for enrollment in Part E, subjects must have received an anti-PD1/PD-L1 as their most recent treatment prior to study entry. The dose level to be administered in Part E will be the combination RP2D as determined in Part C. Part F will evaluate the safety, tolerability, PK, PD, and preliminary clinical activity of IPI-549 in combination with intravenous (IV) nivolumab 240 mg Q2W in a cohort of subjects with triple negative breast cancer (TNBC). One or more cohorts of subjects with additional tumor types may be enrolled if supported by data generated in dose escalation or earlier expansion cohorts. To be eligible for enrollment in Part E, subjects must have no prior anti-PD1/PD-L1 therapy. The dose level to be administered in Part E will be the combination RP2D as determined in Part C. Part G will evaluate the safety, tolerability, PK, PD, and preliminary clinical activity of IPI-549 in combination with intravenous (IV) nivolumab 240 mg Q2W in a cohort of subjects with adrenocortical carcinoma (ACC) and a cohort of subjects with mesothelioma who have received at least first line available therapy. One or more cohorts of subjects with additional tumor types may be enrolled if supported by data generated in dose escalation or earlier expansion cohorts. The dose level to be administered in Part E will be the combination RP2D as determined in Part C. Part H will evaluate the safety, tolerability, PK, and preliminary clinical activity of IPI-549 in combination with IV nivolumab 240 mg Q2W in subjects with advanced cancer with high-circulating MDSCs (ie, ≥ 20.5% as measured by Serametrix CLIA-certified assay); other indication(s) are to be determined. For subject's with a microsatellite instability-high tumor, or tumor type for which anti-PD-1/anti-PD-L1 therapy is considered standard of care, that subject must have previously received an anti-PD-1 or anti-PD-L1 therapy.
Interventions
IPI-549 daily dose administered orally in 28-day cycles (Part A/BC/D/D-Annex/E)
DRUGNivolumab
Nivolumab (240 mg, Q2W) administered intravenously (IV) in 28-day cycles (Part C/D-Annex/E).
Sponsors
Infinity Pharmaceuticals, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
All subjects must meet the following criteria for inclusion: * ≥ 18 years of age * Life expectancy of ≥ 3 months * Histological or cytological evidence of advanced and/or metastatic carcinoma or melanoma , excluding sarcoma * At least 1 measurable disease lesion as defined by RECIST 1.1 * Serum creatinine clearance ≥ 60 mL/min and serum creatinine ≤ 2.0 x the upper limit of normal (ULN) as determined by either of the following: Estimation as calculated by Cockcroft-Gault equation or Direct measurement by 24-hour urine collection * Total bilirubin ≤ 1.5 x ULN (unless elevated due to Gilbert's syndrome) * Aspartate aminotransferase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) ≤ 2.5 x ULN (\<5x ULN if liver metastasis) * Adequate hematological function, defined as absolute neutrophil count ≥1.5 x 109/L, hemoglobin ≥ 9.0 g/dL, and platelet count ≥ 100 x 109/L * Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (corresponds to Karnofsky Performance Status (KPS) ≥ 60%) Subjects entering Part A, B, C, or D must also meet the following additional criterion: • Failure to respond to standard therapy, or for whom no appropriate therapies are available (based on the judgement of the Investigator) Subjects entering Part D, E, F or G must also meet the following additional criterion: • Willing to undergo 1 pre-treatment and 1 on-treatment tumor biopsy Subjects entering Part E must also meet the following additional criteria: * Histological or cytological evidence of NSCLC, melanoma, , human papillomavirus (HPV) positive or HPV negative SCCHN (oral cavity, pharynx, hypopharynx, larynx, nasopharyngeal \[including undifferentiated nasopharyngeal carcinoma\]), or another tumor type to be determined * Failure to respond to standard therapy, or for whom no appropriate therapies are available (based on the judgment of the Investigator The most recent treatment prior to study entry must be an anti-PD-1 or anti-PD-L1 antibody given as either monotherapy or in combination * Subjects with NSCLC Tumors that harbor an actionable genetic alteration for which there is a corresponding approved therapy for that specific alteration (including but not limited to alterations in EGFR, ALK, and ROS) must have progressed on, or had intolerance to, the respective therapy Subjects entering Part F must also meet the following additional criteria: * Histological or cytological evidence of estrogen-receptor negative (ER-), progesterone receptor negative (PgR-) and human epidermal growth factor-2 receptor negative (HER2-) Breast Cancer by local laboratory testing, based on last available tumor tissue; or another tumor type to be determined * ER/PgR negativity to follow local guidelines * If IHC HER2 2+, a negative FISH test is required * Inflammatory triple negative breast cancer is allowed * Must have received and failed/progressed a cytotoxic chemotherapy as first line therapy per standard of care * No prior anti-PD-1 or anti-PD-L1 therapy Subjects entering Part G must also meet the following additional criteria: * Histological or cytological evidence of ACC, mesothelioma, or another tumor type to be determined * Both pleural and peritoneal mesothelioma are allowed * Epithelioid, sarcomatoid, or biphasic mesothelioma subtypes are allowed * Progression after at least first line available therapy Patients entering Part H must also meet the following additional criteria: High-circulating MDSCs, currently defined for this study as MDSCs ≥ 20.5% as measured by CLIA-certified Serametrix assay Microsatellite status of tumor has been determined Patients with tumors that are microsatellite instability-high must have previously received an anti-PD-1/anti-PD-L1 therapy and progressed on therapy If patient's tumor type is one for which anti-PD-1/anti-PD-L1 therapy is standard of care, patient must have previously received an anti-PD-1 or anti-PD-L1 therapy and progressed while on that therapy
Exclusion criteria
Subjects are to be excluded from the study if they meet any of the following criteria: * Severe allergic or anaphylactic reaction to any monoclonal antibody therapy, murine protein, or known hypersensitivity to any excipient in the study drugs * Major surgery within 4 weeks prior to Screening * Subjects who have been treated with chemotherapy, biologic therapy, or other investigational agent within \< 5 times the half-life of the agent or \< 28 days (whichever is shorter) of starting study drug NOTE: Subjects whose immediate prior treatment was with nivolumab may start study drug 2 weeks after the last dose of nivolumab * Symptomatic or untreated brain metastases * Primary central nervous system (CNS) malignancy * Infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C virus * Ongoing treatment with chronic immunosuppressants (eg, cyclosporine) or systemic steroids * Ongoing systemic bacterial, fungal, or viral infections at Screening NOTE: Subjects on antimicrobial, antifungal, or antiviral prophylaxis are not specifically excluded if all other inclusion/
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Part D/E: Adverse Events (AE) and safety laboratory values | Number of patients with Clinically significant abnormal laboratory values and adverse events that are related to treatment from date of initial dose until 30 days after last dose of IPI-549 and 100 days after the last dose of Nivolumab |
| Part A/B/C: Dose Limiting Toxicities (DLT) | From date of initial dose until up to 28 days for IPI-549 |
Secondary
| Measure | Time frame |
|---|---|
| Part A/B: Overall response rate (ORR), complete response/remission (CR) or partial response/remission (PR) | Responses Assessed in Cycle 3 and every odd cycle through study completion, an average of 1 year |
| Part A/B: Duration of response (DoR) | Responses Assessed in Cycle 3 and every odd cycle through study completion, an average of 1 year |
| Part C: Adverse Events (AE) and safety laboratory values | Number of patients with Clinically significant abnormal laboratory values and adverse events that are related to treatment assessed during every visit for duration of study participation which is estimated to be 24 months |
| Part C: Plasma concentrations of IPI-549 (metabolites as appropriate) | Assessed during Days 1- 2 of Cycles 1 and 2 |
| Part C: Overall Response Rate (ORR) | Responses Assessed in Cycle 3 and every odd cycle through study completion, an average of 1 year |
| Part C: Duration of Response (DoR) | Responses Assessed in Cycle 3 and every odd cycle through study completion, an average of 1 year |
| Part D: Overall Response Rate (ORR) | Responses Assessed in Cycle 3 and every odd cycle through study completion, an average of 1 year |
| Part D: Duration of Response (DoR) | Responses Assessed in Cycle 3 and every odd cycle through study completion, an average of 1 year |
| Part D: Progression-Free Survival (PFS) | Responses Assessed in Cycle 3 and every odd cycle through study completion, an average of 1 year |
| Part D: Overall Survival (OS) | Estimated to be 3 years |
| Part D: Plasma concentrations of IPI-549 (and metabolites, as appropriate) | Assessed during Days 1- 15 of Cycles 1 and 2, Assessed During Day 1 of Cycles 3 and 4 |
| Part E:Overall Response Rate (ORR) | Responses Assessed in Cycle 3 and every odd cycle through study completion, an average of 1 year |
| Part F:Overall Response Rate (ORR) | Responses Assessed in Cycle 3 and every odd cycle through study completion, an average of 1 year |
| Part A/B: Adverse Events (AE) and safety laboratory values | Number of patients with Clinically significant abnormal laboratory values and adverse events that are related to treatment assessed during every visit for duration of study participation which is estimated to be 24 months |
| Part E: Duration of Response (DoR) | Responses Assessed in Cycle 3 and every odd cycle through study completion, an average of 1 year |
| Part F: Duration of Response (DoR) | Responses Assessed in Cycle 3 and every odd cycle through study completion, an average of 1 year |
| Part G: Duration of Response (DoR) | Responses Assessed in Cycle 3 and every odd cycle through study completion, an average of 1 year |
| Part E: Progression Free Survival (PFS) | Responses Assessed in Cycle 3 and every odd cycle through study completion, an average of 1 year |
| Part F: Progression Free Survival (PFS) | Responses Assessed in Cycle 3 and every odd cycle through study completion, an average of 1 year |
| Part G: Progression Free Survival (PFS) | Responses Assessed in Cycle 3 and every odd cycle through study completion, an average of 1 year |
| Part E: Overall Survival (OS) | Estimated to be 3 years |
| Part F: Overall Survival (OS) | Estimated to be 3 years |
| Part G: Overall Survival (OS) | Estimated to be 3 years |
| Part E: Plasma concentrations of IPI-549 (and metabolites, as appropriate) | Assessed during Days 1- 2 of Cycles 1 and 2 |
| Part F: Plasma concentrations of IPI-549 (and metabolites, as appropriate) | Assessed during Days 1- 2 of Cycles 1 and 2 |
| Part G: Plasma concentrations of IPI-549 (and metabolites, as appropriate) | Assessed during Days 1- 2 of Cycles 1 and 2 |
| Part G:Overall Response Rate (ORR) | Responses Assessed in Cycle 3 and every odd cycle through study completion, an average of 1 year |
| Part A/B: Plasma concentrations of IPI-549 (metabolites, as appropriate) | Assessed during Days 1- 22 of Cycles 1 and 2, Assessed During Day 1 of Cycles 3 and 4 |
Countries
United States
Outcome results
None listed