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).
1. ≥18 years of age.
2. 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.
3. Willing and able to comply with scheduled visits, treatment schedule, laboratory
tests, fresh tumor biopsies, and all other protocol requirements.
4. 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.
5. 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.
6. 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.
7. Eastern Cooperative Oncology Group (ECOG) performance status ≤1.
8. Life expectancy ≥12 weeks.
9. Baseline laboratory values must meet the following criteria within 14 days of the
1. 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).
2. Calculated creatinine clearance ≥30 mL/min.
3. 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.
4. Total bilirubin ≤1.25 × ULN (unless elevated due to Gilbert's syndrome who can
have total bilirubin <3.0 mg/dL).
5. 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
6. Serum albumin >2.5 g/dL
10. Women of childbearing potential (WOCBP) must have a negative serum or urine β human
chorionic gonadotropin (βhCG) 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.
11. Women must not be breastfeeding.
12. 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:
1. 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)
1. HER2 negativity defined as either of the following by local laboratory assessment
2. ER and PR negativity defined as <1% of cells expressing hormonal receptors via
2. 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:
1. Men or women with histologically documented unresectable advanced or metastatic RCC
with clear-cell histology.
2. 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.
1. WOCBP who are pregnant or breastfeeding.
2. Women with a positive pregnancy test at enrollment or prior to administration of study
3. 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
4. Any history of, or currently active, brain or leptomeningeal metastases.
5. 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.
6. Baseline QT interval corrected with Fridericia's method (QTcF) >480 ms.
7. 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.
8. Active tuberculosis.
9. Ongoing systemic bacterial, fungal, or viral infections at Screening.
10. Positive test for human immunodeficiency virus (HIV).
11. 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.
12. Dependence on continuous supplemental oxygen use.
13. 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.
14. 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.
15. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster
ovary cells, or any of the study drug components.
16. History of severe allergic, anaphylactic, or other hypersensitivity reactions to
chimeric or humanized antibodies or fusion proteins.
17. History of stroke, transient ischemic attack, or ventricular arrhythmia requiring
medication or mechanical control within the last 6 months prior to Screening.
18. 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.
19. 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, Sjögren's syndrome, Guillain-Barré syndrome,
multiple sclerosis, vasculitis, or glomerulonephritis.
20. 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.
21. 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.
22. Prior allogeneic stem cell or solid organ transplantation.
23. 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.
24. 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.
25. 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.
26. 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.
27. 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.
28. Administration of any of the following within 1 week prior to the administration of
1. Strong inhibitors or inducers of cytochrome P450 (CYP) 3A4, including grapefruit,
grapefruit juice and herbal supplements.
2. Warfarin, phenytoin, or other substrates of CYP2C8 or CYP2C9 with a narrow
3. P-glycoprotein (P-gp) inhibitors.
29. 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
1. 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.
2. Uncontrolled tumor-related pain.
3. 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
1. Inadequately controlled hypertension (systolic blood pressure >150 mmHg and/or
diastolic blood pressure >100 mmHg or prior history of hypertensive crisis or
2. Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or
recent peripheral arterial thrombosis) within 6 months prior to Cycle 1, Day 1.
3. Evidence of bleeding diathesis or clinically significant coagulopathy (in the absence
of therapeutic anticoagulation).
4. Current or recent (within 10 calendar days prior to Cycle 1, Day 1) use of
dipyridamole, clopidogrel, or cilostazol.
5. History of abdominal or tracheoesophageal fistula or gastrointestinal perforation
within 5 months prior to Cycle 1, Day 1.
6. Clinical signs or symptoms of gastrointestinal obstruction or requirement for routine
parenteral hydration, parenteral nutrition, or tube feeding.
7. Evidence of abdominal free air not explained by paracentesis or recent surgical
8. Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture.
9. 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.