Evaluation of IPI-549 Combined With Front-line Treatments in Pts. With Triple-Negative Breast Cancer or Renal Cell Carcinoma (MARIO-3)

  • STATUS
    Recruiting
  • End date
    Aug 1, 2022
  • participants needed
    90
  • sponsor
    Infinity Pharmaceuticals, Inc.
Updated on 27 January 2021
ct scan
platelet count
paclitaxel
gonadotropin
cancer
monoclonal antibodies
systemic therapy
estrogen
measurable disease
carcinoma
breast cancer
avastin
vegf
growth factor
gilbert's syndrome
progesterone
metastasis
neutrophil count
liver metastasis
immunohistochemistry
epidermal growth factor receptor
HER2
EGFR
bevacizumab
biomarker analysis
pd-l1
programmed cell death 1 ligand 1
triple negative breast cancer
progesterone receptor
erbb2
epidermal growth factor
estrogen receptor
taxane
triple-negative breast cancer
atezolizumab
immunostimulant
mammogram
core needle biopsy

Summary

MARIO-3 is a Phase 2 multi-arm combination cohort study designed to evaluate IPI-549, Infinity Pharmaceutical's first-in-class, oral immuno-oncology product candidate targeting immune-suppressive tumor-associated myeloid cells through selective inhibition of phosphoinositide-3-kinase (PI3K)-gamma, in combinations with Tecentriq and Abraxane (nab-paclitaxel) in front-line triple negative breast cancer (TNBC) and in combination with Tecentriq and Avastin (bevacizumab) in front-line renal cell cancer (RCC).

Description

MARIO-3 (Macrophage Reprogramming in Immuno-Oncology) is a prospective Phase 2 multi-arm, multicenter, open-label, combination cohort study designed to evaluate IPI-549, Infinity Pharmaceutical's first-in-class, oral immuno-oncology product candidate targeting immune-suppressive tumor-associated myeloid cells through selective inhibition of phosphoinositide-3-kinase (PI3K)-gamma. IPI-549 will be administered in combinations with Tecentriq and Abraxane (nab-paclitaxel) in front-line triple negative breast cancer (TNBC) and in combination with Tecentriq and Avastin (bevacizumab) in front-line renal cell cancer (RCC).

This study will enroll approximately 90 treatment-nave patients across the following disease cohorts. Cohort A will be composed of patients with locally advanced and/or metastatic triple-negative breast cancer (TNBC). Cohort B will be composed of patients with locally advanced and/or metastatic renal cell carcinoma (RCC).

The primary objective of MARIO-3 is to evaluate the complete response (CR) rate per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 following combination treatment with IPI-549 and front-line treatment in patients with TNBC and RCC. Its secondary objectives include evaluation of the safety, objective response rate (ORR), time to CR (TTCR), time to response (TTR), duration of CR (DOCR), duration of response (DOR), and progression-free survival (PFS).

Details
Condition Adenocarcinoma, Malignant neoplasm of kidney, Breast Cancer, Renal Cell Carcinoma, Breast Cancer Diagnosis, Kidney Cancer, Malignant Adenoma, Renal Cell Cancer, Renal Cancer, breast carcinoma, clear cell renal cell carcinoma, cancer, breast
Treatment bevacizumab, Nab-paclitaxel, Atezolizumab, IPI-549, IPI-549 (eganelisib)
Clinical Study IdentifierNCT03961698
SponsorInfinity Pharmaceuticals, Inc.
Last Modified on27 January 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

18 years of age
Have signed and dated an independent review board (IRB)/independent ethics committee (IEC) approved informed consent form (ICF) in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol-related procedures that are not part of normal patient care
Willing and able to comply with scheduled visits, treatment schedule, laboratory tests, fresh tumor biopsies, and all other protocol requirements
At least 1 measurable disease lesion by computed tomography (CT) or magnetic resonance imaging (MRI) as defined by RECIST v1.1 performed within 1 week prior to first dose
Willing to undergo one pre-treatment core biopsy (unless archival tumor tissue is available within 3 months of first dose) and one on-treatment tumor biopsy, unless not safe or medically feasible. If the patient is unwilling to undergo biopsy, they may be eligible with approval of the medical monitor
Evaluable tumor tissue (archived [without time constraints] or new biopsy) must be provided for biomarker analysis, which will include PD-L1 expression level using immunohistochemistry (IHC) to measure specific PD-L1 signals in tumor-infiltrating immune cells (ICs). Results are not required prior to start of study treatment
Eastern Cooperative Oncology Group (ECOG) performance status 1
Life expectancy 12 weeks
Baseline laboratory values must meet the following criteria within 14 days of the first dose
Adequate hematologic function, defined as white blood cell (WBC) count 2.0 109/L, absolute neutrophil count 1.5 109/L (without granulocyte colony-stimulating factor [GCSF] support within 2 weeks prior to Cycle 1, Day 1), lymphocyte count 0.5 109/L, hemoglobin 9.0 g/dL (patients may be transfused or receive erythropoietic treatment to meet this criterion), and platelet count 100 109/L (without transfusion within 2 weeks prior to Cycle 1, Day 1)
Calculated creatinine clearance 30 mL/min
Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) <2.5 upper limit of normal (ULN). ALT and AST 5 ULN if documented liver metastasis. ALP 5 ULN if documented bone or liver metastasis
Total bilirubin 1.25 ULN (unless elevated due to Gilbert's syndrome who can have total bilirubin <3.0 mg/dL)
International normalized ratio (INR) and activated partial thromboplastin time (aPTT) 1.5 ULN. This applies to patients who are not receiving therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be on a stable dose
Serum albumin >2.5 g/dL
Women of childbearing potential (WOCBP) must have a negative serum or urine human chorionic gonadotropin (hCG) pregnancy test within 1 week before administration of study drug WOCBP is defined as any female who has 12 months of non-therapy induced amenorrhea or is surgically sterile
Women must not be breastfeeding
Willingness of male and female patients who are not surgically sterile or postmenopausal to use medically acceptable methods of birth control for the duration of study treatment, including 30 days after the last dose of IPI-549 and of nab-paclitaxel, or 6 months after the last dose of atezolizumab or bevacizumab, whichever is later. Male patients must refrain from donating sperm for these same periods. Male patients with a pregnant female partner must agree to remain abstinent or use a condom during the treatment period and for the duration of the pregnancy
Patients in Cohort A must meet the following additional criteria for
inclusion
Women with metastatic or locally advanced (not amenable to resection with curative intent), histologically documented TNBC, i.e., absence of human epidermal growth factor receptor 2 (HER2), estrogen receptor (ER) and progesterone receptor (PR)
expression
HER2 negativity defined as either of the following by local laboratory assessment
ER and PR negativity defined as <1% of cells expressing hormonal receptors via IHC analysis
No prior chemotherapy or targeted systemic therapy for inoperable locally advanced or metastatic TNBC. Radiation therapy for metastatic disease is permitted. There is no required minimum washout period for radiation therapy. Patients should be recovered from the effects of radiation. Prior chemotherapy (including taxanes) in the neoadjuvant or adjuvant setting is allowable if treatment was completed 12 months prior to randomization
Patients in Cohort B must meet the following additional criteria for
inclusion
Men or women with histologically documented unresectable advanced or metastatic RCC with clear-cell histology
No prior treatment with active or experimental systemic agents, including treatment in the neoadjuvant or adjuvant setting. Prior radiotherapy is permitted but must not have been administered within 14 days of Cycle 1, Day 1

Exclusion Criteria

WOCBP who are pregnant or breastfeeding
Women with a positive pregnancy test at enrollment or prior to administration of study medication
Any serious or uncontrolled medical disorder that, in the opinion of the Investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the patient to receive protocol therapy, or interfere with the interpretation of study results, including significant liver disease (such as cirrhosis, uncontrolled major seizure disorder, or superior vena cava syndrome)
Any history of, or currently active, brain or leptomeningeal metastases
Significant cardiovascular disease, such as New York Heart Association (NYHA) cardiac disease (Class II or greater), myocardial infarction within 3 months prior to randomization, unstable arrhythmias, or unstable angina. Patients with a known left ventricular ejection fraction (LVEF) <40% will be excluded. Patients with known coronary artery disease, congestive heart failure not meeting the above criteria, or LVEF <50% must be on a stable medical regimen that is optimized in the opinion of the treating physician, in consultation with a cardiologist if appropriate
Baseline QT interval corrected with Fridericia's method (QTcF) >480 ms
Major surgical procedure within 4 weeks prior to enrollment or anticipation of the need for a major surgical procedure during the course of the study other than for diagnosis. Placement of central venous access catheter(s) (e.g., port or similar) is not considered a major surgical procedure and is therefore permitted
Active tuberculosis
Ongoing systemic bacterial, fungal, or viral infections at Screening
Positive test for human immunodeficiency virus (HIV)
Active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C. Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen [anti-HBc] antibody test) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA
Dependence on continuous supplemental oxygen use
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently). Patients with indwelling catheters (e.g., PleurX) are allowed
Uncontrolled hypercalcemia (>1.5 mmol/L ionized calcium or calcium >12 mg/dL or corrected serum calcium >ULN) or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy. Patients who are receiving denosumab must discontinue denosumab use and replace it with a bisphosphonate instead while on study. There is no required minimum washout period for denosumab. Patients who are receiving bisphosphonate therapy specifically to prevent skeletal events and who do not have a history of clinically significant hypercalcemia are eligible
Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells, or any of the study drug components
History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
History of stroke, transient ischemic attack, or ventricular arrhythmia requiring medication or mechanical control within the last 6 months prior to Screening
Other prior malignancy active within the previous 5 years except for local or organ confined early stage cancer that has been definitively treated with curative intent, does not require ongoing treatment, has no evidence of residual active disease, and has a negligible risk of recurrence and is therefore unlikely to interfere with the primary and secondary endpoints of the study, including response rate and safety
History of autoimmune disease, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjgren's syndrome, Guillain-Barr syndrome, multiple sclerosis, vasculitis, or glomerulonephritis
History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest CT scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted
Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease
Prior allogeneic stem cell or solid organ transplantation
Administration of a live or attenuated vaccine within 4 weeks of first dose of study drug or anticipation that such a live or attenuated vaccine will be required during the study or within 5 months following the last dose of atezolizumab
Prior therapy with experimental anti-tumor vaccines; any T cell co-stimulation or checkpoint pathways, such as anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, including ipilimumab, or other medicines specifically targeting the T cell; or IPI-549
Treatment with systemic immunostimulatory agents (including but not limited to interferons or IL-2) within 4 weeks or 5 half-lives of the drug (whichever is shorter) prior to enrollment
Treatment with systemic corticosteroids or other systemic immunosuppressive medications (including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [TNF] agents) within 2 weeks prior to randomization, or anticipated requirement for systemic immunosuppressive medications during the trial
Treatment with botanical preparations (e.g., herbal supplements or traditional Chinese medicines) intended for general health support or to treat the disease under study within 2 weeks prior to randomization
Administration of any of the following within 1 week prior to the administration of study drug
Strong inhibitors or inducers of cytochrome P450 (CYP) 3A4, including grapefruit, grapefruit juice and herbal supplements
Warfarin, phenytoin, or other substrates of CYP2C8 or CYP2C9 with a narrow therapeutic range
P-glycoprotein (P-gp) inhibitors
Prior surgery or gastrointestinal dysfunction that may affect drug absorption (e.g., gastric bypass surgery, gastrectomy)
Patients in Cohort A are to be excluded from the study if they meet any of the
following
criteria
Spinal cord compression not definitively treated with surgery and/or radiation, or previously diagnosed and treated spinal cord compression without evidence that disease has been clinically stable for >2 weeks prior to first dose of study treatment
Uncontrolled tumor-related pain
Known hypersensitivity to nab-paclitaxel or to any of the excipients
Patients in Cohort B are to be excluded from the study if they meet any of the
following
criteria
Inadequately controlled hypertension (systolic blood pressure >150 mmHg and/or diastolic blood pressure >100 mmHg or prior history of hypertensive crisis or hypertensive encephalopathy
Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to Cycle 1, Day 1
Evidence of bleeding diathesis or clinically significant coagulopathy (in the absence of therapeutic anticoagulation)
Current or recent (within 10 calendar days prior to Cycle 1, Day 1) use of dipyridamole, clopidogrel, or cilostazol
History of abdominal or tracheoesophageal fistula or gastrointestinal perforation within 5 months prior to Cycle 1, Day 1
Clinical signs or symptoms of gastrointestinal obstruction or requirement for routine parenteral hydration, parenteral nutrition, or tube feeding
Evidence of abdominal free air not explained by paracentesis or recent surgical procedure
Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture
Proteinuria, as demonstrated by urine dipstick or >1.0 g of protein in a 24-hour urine collection. All patients with 2+ protein on dipstick urinalysis at baseline must undergo a 24-hour urine collection for protein
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