Clinical Trials /

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

NCT03961698

Description:

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).

Related Conditions:
  • Breast Carcinoma
  • Clear Cell Renal Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Evaluation of IPI-549 Combined With Front-line Treatments in Pts. With Triple-Negative Breast Cancer or Renal Cell Carcinoma (MARIO-3)
  • Official Title: A Phase 2, Multi-arm, Multicenter, Open-label Study to Evaluate the Efficacy and Safety of IPI-549 Administered in Combination With Front-line Treatment Regimens in Patients With Locally Advanced and/or Metastatic Triple-Negative Breast Cancer or Renal Cell Carcinoma

Clinical Trial IDs

  • ORG STUDY ID: IPI-549-03
  • NCT ID: NCT03961698

Conditions

  • Breast Cancer
  • Renal Cell Carcinoma

Interventions

DrugSynonymsArms
IPI-549Cohort A (TNBC)
AtezolizumabTecentriqCohort A (TNBC)
nab-paclitaxelAbraxaneCohort A (TNBC)
BevacizumabAvastinCohort B (RCC)

Purpose

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).

Detailed 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-naïve 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).
    

Trial Arms

NameTypeDescriptionInterventions
Cohort A (TNBC)ExperimentalIPI-549 in combination with front-line treatment. Cohort A will include two sub-cohorts: Cohorts A1 and A2. Cohort A1: Approximately 30 patients with locally advanced and/or metastatic TNBC with programmed death-ligand 1 (PDL1) positive disease based on immunohistochemistry (IHC) defined as IC1/2/3. Cohort A2: Approximately 30 patients with locally advanced and/or metastatic TNBC with PDL1 negative disease based on IHC defined as IC0.
  • IPI-549
  • Atezolizumab
  • nab-paclitaxel
Cohort B (RCC)ExperimentalIPI-549 in combination with front-line treatment. Cohort B will include two sub-cohorts: Cohorts B1 and B2. Cohort B1: Approximately 15 patients with locally advanced and/or metastatic RCC, with PDL1 positive disease based on IHC defined as IC1/2/3. Cohort B2: Approximately 15 patients with locally advanced and/or metastatic RCC, with PDL1 negative disease based on IHC defined as IC0.
  • IPI-549
  • Atezolizumab
  • Bevacizumab

Eligibility Criteria

        Inclusion Criteria:

          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
             first dose:

               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
                  stable dose.

               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)
             expression:

               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
                  IHC analysis

          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.

        Exclusion Criteria:

          1. WOCBP who are pregnant or breastfeeding.

          2. Women with a positive pregnancy test at enrollment or prior to administration of study
             medication.

          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
             syndrome).

          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
             study drug:

               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
                  therapeutic range.

               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
        criteria:

          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
        criteria:

          1. Inadequately controlled hypertension (systolic blood pressure >150 mmHg and/or
             diastolic blood pressure >100 mmHg or prior history of hypertensive crisis or
             hypertensive encephalopathy.

          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
             procedure.

          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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Complete Response (CR) rate (change in target lesion size).
Time Frame:CR rate assessments will be conducted through month 12 for Cohort A (TNBC) and through month 18 for Cohort B (RCC) until unacceptable toxicity, confirmed progression of disease, withdrawal of consent, or other treatment discontinuation criteria are met.
Safety Issue:
Description:Complete Response (CR) rate is defined per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as disappearance of all target and non-target lesions.

Secondary Outcome Measures

Measure:Incidence of treatment-emergent adverse events (TEAEs)
Time Frame:TEAE assessments will be conducted from screening through month 12 for Cohort A (TNBC) and from screening through month 18 for Cohort B (RCC). Additional assessments will be conducted 30 days and 90 days from last dose.
Safety Issue:
Description:Treatment emergent adverse events (TEAE) are undesirable events not present prior to medical treatment, or an already present event that worsens either in intensity or frequency following the treatment.
Measure:Incidence of serious adverse events (SAEs), including deaths
Time Frame:SAE assessments will be conducted from screening through month 12 for Cohort A (TNBC) and from screening through month 18 for Cohort B (RCC). Additional assessments will be conducted 30 days and 90 days from last dose.
Safety Issue:
Description:Serious adverse events include death, life-threatening events, initial or prolonged hospitalization, disability or permanent damage, or require an intervention to prevent impairment.
Measure:Incidence of adverse events (AEs) leading to treatment discontinuation
Time Frame:AE assessments will be conducted from screening through month 12 for Cohort A (TNBC) and from screening through month 18 for Cohort B (RCC). Additional assessments will be conducted 30 days and 90 days from last dose.
Safety Issue:
Description:An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event (AE) can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.
Measure:Changes from baseline in electrocardiograms (ECGs)
Time Frame:ECG assessments will be performed from screening through month 12 for Cohort A (TNBC) and from screening through month 18 for Cohort B (RCC).
Safety Issue:
Description:ECGs assess heart problems by measuring the electrical activity generated by the heart as it contracts. The components that will be assessed during the ECG are P wave, QRS complex, ST segment, and T wave.
Measure:Objective response rate (ORR)
Time Frame:ORR will be assessed from screening through month 12 for Cohort A (TNBC) and from screening through month 18 for Cohort B (RCC).
Safety Issue:
Description:ORR is defined as best response of CR or partial response (PR), as determined by RECIST v1.1.
Measure:Time to Complete Remission (TTCR)
Time Frame:TTCR will be assessed from screening through month 12 for Cohort A (TNBC) and from screening through month 18 for Cohort B (RCC).
Safety Issue:
Description:TTCR is defined as the time from the first dose of study treatment to CR.
Measure:Time to response (TTR)
Time Frame:TTR will be assessed from screening through month 12 for Cohort A (TNBC) and from screening through month 18 for Cohort B (RCC).
Safety Issue:
Description:TTR is defined as the time from the first dose of study treatment to first objective response (CR or PR) in patients with CR or PR.
Measure:Duration of Complete Remission (DOCR)
Time Frame:DOCR will be assessed from screening through month 12 for Cohort A (TNBC) and from screening through month 18 for Cohort B (RCC).
Safety Issue:
Description:DOCR is defined as the time from the first CR to documented disease progression in patients with CR.
Measure:Duration of response (DOR)
Time Frame:DOR will be assessed from screening through month 12 for Cohort A (TNBC) and from screening through month 18 for Cohort B (RCC).
Safety Issue:
Description:DOR is defined as the time from the first objective response (CR or PR) to documented disease progression in patients with CR or PR.
Measure:Progression-free survival (PFS)
Time Frame:PFS will be assessed from screening through month 12 for Cohort A (TNBC) and from screening through month 18 for Cohort B (RCC).
Safety Issue:
Description:PFS is defined as the time from the first dose of study treatment to documented disease progression or death due to any cause.
Measure:Population Pharmacokinetics (PK) of IPI-549
Time Frame:PK assessments will be performed on day 1 of each 28-day cycle through cycle 2 for cohort A (TNBC) at and on day 1 of each 21-day cycle through cycle 2 for cohort B (RCC).
Safety Issue:
Description:Population PK estimates (variability in drug concentrations within the study population measured in ng/mL) includes inter- and intra-subject variability and covariate effects.
Measure:Pharmacokinetics (PK) of Atezolizumab
Time Frame:PK assessments will be performed on day 1 of cycle 1, on day 1 of cycles 2 through 4, C8D1, C16D1 for both cohorts. Cohort A (TNBC) has a 28-day cycle and cohort B (RCC) has a 21-day cycle.
Safety Issue:
Description:Concentration of Atezolizumab in the blood at predose measured in ug/mL.
Measure:Changes from baseline in pulse rate
Time Frame:Pulse rate will be assessed from screening through month 12 for Cohort A (TNBC) and from screening through month 18 for Cohort B (RCC).
Safety Issue:
Description:Pulse rate as measured in beats per minute (bpm).
Measure:Changes from baseline in temperature
Time Frame:Temperature will be assessed from screening through month 12 for Cohort A (TNBC) and from screening through month 18 for Cohort B (RCC).
Safety Issue:
Description:Temperature as measured in celsius.
Measure:Changes from baseline in respiration rate
Time Frame:Respiration rate will be assessed from screening through month 12 for Cohort A (TNBC) and from screening through month 18 for Cohort B (RCC).
Safety Issue:
Description:Respiration rate as measured in breaths per minute.
Measure:Changes from baseline in blood pressure
Time Frame:Blood pressure will be assessed from screening through month 12 for Cohort A (TNBC) and from screening through month 18 for Cohort B (RCC).
Safety Issue:
Description:Systolic and diastolic blood pressure as measured in mmHg.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Infinity Pharmaceuticals, Inc.

Trial Keywords

  • Phase 2
  • PI3K
  • IPI-549
  • Advanced Solid Tumor
  • Triple Negative Breast Cancer (TNBC)
  • Renal Cell Carcinoma (RCC)
  • PD-L1
  • Myeloid-Derived Suppressor Cells (MDSCs)
  • Front-Line Treatment

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