Study to Evaluate the Efficacy/Safety of IPI-549 in Combination With Nivolumab in Patients With Advanced Urothelial Carcinoma (MARIO-275)

A Phase 2, Multicenter, Randomized, Double-Blind, Active-Control Study to Evaluate the Efficacy and Safety of Nivolumab Administered in Combination With IPI-549 Compared to Nivolumab Monotherapy in the Treatment of Patients With Immune Therapy-Naïve, Advanced Urothelial Carcinoma

The purpose of this study is to measure the effect of IPI-549 in combination with nivolumab when compared to nivolumab monotherapy in advanced urothelial cancer patients.

Study Overview

• Status: Completed
• Conditions: Solid Tumor; Bladder Cancer; Advanced Cancer; Urothelial Carcinoma
• Intervention / Treatment: Drug: IPI-549 (eganelisib); Drug: Nivolumab; Drug: Placebos

Detailed Description

Study IPI-549-02 is a multi-national, prospective, randomized, active-control Phase II trial to evaluate the efficacy and safety of IPI 549 administered in combination with nivolumab compared to nivolumab monotherapy.

The study will enroll approximately 160 checkpoint-naïve, advanced urothelial cancer patients who have progressed or recurred following treatment with platinum-based chemotherapy. Patients will be randomized 2:1 to receive intravenous (IV) nivolumab 480 mg every 4 weeks (Q4W) in combination with oral (PO) IPI 549 40 mg once daily (QD) or IV nivolumab 480 mg Q4W in combination with placebo PO QD.

Eligible patients who have confirmed progression of disease during treatment with nivolumab monotherapy may crossover to the combination treatment arm.

• Study Type: Interventional
• Enrollment (Actual): 49
• Phase: Phase 2

Contacts and Locations

Study Locations

• Czechia
  • Praha, Czechia, 140 59
    • Onkologicka klinika
• France
  • Lille, France, 59020
    • Centre Oscar Lambret
  • Marseille, France, 13009
    • Institut Paoli-Calmettes
  • Nice, France, 06189
    • Centre Antoine Lacassagne
  • Strasbourg, France, 67000
    • CHU de Strasbourg
  • Toulouse, France, 31300
    • Institut Claudius Regaud
• Italy
  • Candiolo, Italy, 10060
    • Istituto per la Ricerca e la Cura del Cancro (IRCC)
  • Meldola, Italy, 47104
    • Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori
  • Napoli, Italy, 80131
    • Istituto Nazionale dei Tumori
• Poland
  • Racibórz, Poland, 47-400
    • Dzienny Oddzial Chemioterapii
  • Skorzewo, Poland, 60-185
    • EXAMEN sp
  • Łódź, Poland, 93-153
    • Oddzial Chorob Rozrostowych Wojewodzki Szpital
• Serbia
  • Belgrade, Serbia, 11 000
    • Clinical Centre of Serbia
  • Sremska Kamenica, Serbia, 21 204
    • Institute for oncology of Vojvodina
• Spain
  • Barcelona, Spain, 08907
    • ICO Institute Catalan of Oncology
  • Barcelona, Spain, 8005
    • Hospital de Sant Creu i Sant Pau
  • Bilbao, Spain, 48180
    • IMQ Zorrotzaurre
  • Madrid, Spain, 28034
    • Hospital Ramon y Cajal
  • Madrid, Spain, 28033
    • MD Anderson Cancer Center Madrid
  • Madrid, Spain, 28050
    • Hospital Universitatio HM Sanchinarro
  • Oviedo, Spain, 33011
    • Hospital Universitario Central de Asturias
  • Sevilla, Spain, 41013
    • Hospital Universitario
• United States
  • Indiana
    • Fort Wayne, Indiana, United States, 46845
      • Parkview Physicians
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of MD - Greenebaum Comprehensive Cancer Center
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Karmanos Cancer Center
  • Minnesota
    • Saint Cloud, Minnesota, United States, 56303
      • Coborn Cancer Center
  • New York
    • Bronx, New York, United States, 10461
      • Montefiore Medical Center
  • South Carolina
    • Greenville, South Carolina, United States, 29607
      • Bon Secours St. Francis Cancer Center
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Tennessee Oncology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histologically or cytologically confirmed urothelial carcinoma of the renal pelvis, ureter, bladder, or urethra
• Measurable disease by CT or MRI as defined by RECIST v1.1
• Disease progression or recurrence after treatment:
• i) With at least 1 platinum-based chemotherapy regimen for the treatment of metastatic (Stage IV) or locally advanced unresectable disease; or
• ii) With disease recurrence within 1 year of completing a platinum-based neoadjuvant or adjuvant therapy
• Subject that have received more than 2 prior lines of chemotherapy must not have liver metastases
• Tumor tissues (archived or new biopsy) must be provided for biomarker analysis
• Eastern Cooperative Oncology Group (ECOG) performance status ≤1
• Blood sample must be provided for mMDSC levels for randomization into the study

Exclusion Criteria:

• Active brain metastases or leptomeningeal metastases
• Any serious or uncontrolled medical disorder that may interfere with study treatment/interpretation
• Prior malignancy active within the previous 3 years except for local or organ confined early stage cancer that has been apparently cured
• Active, known, or suspected autoimmune disease
• A condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 day of study drug administration
• Prior therapy with anti-tumor vaccines, any T cell co-stimulation or checkpoint pathways, or IPI-549
• Prior surgery or gastrointestinal dysfunction that may affect drug absorption
• Past medical history of interstitial lung disease
• History of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia requiring medication or mechanical control
• Positive test for hepatitis B, C or HIV
• Dependent on continuous supplemental oxygen

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: IPI-549 + Nivolumab; Participants receive IPI-549 orally (PO) daily in combination with nivolumab IV infusion every 4 weeks	Drug: IPI-549 (eganelisib); IPI-549 (40mg QD) administered orally in 28-day cycles; Other Names: IPI549; Drug: Nivolumab; Nivolumab (480mg Q4W) administered intravenously (IV) in 28-day cycles; Other Names: OPDIVO®
Active Comparator: Placebo + Nivolumab; Participants receive placebo orally (PO) daily in combination with nivolumab IV infusion every 4 weeks	Drug: Nivolumab; Nivolumab (480mg Q4W) administered intravenously (IV) in 28-day cycles; Other Names: OPDIVO®; Drug: Placebos; Placebo administered orally in 28-day cycles; Other Names: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR) per RECISTv1.1	ORR is defined as best response of complete response (CR) or partial response (PR) as measured by RECIST v1.1. RECIST 1.1 = Response Evaluation Criteria in Solid Tumors. CR= Disappearance of all extranodal target lesions. All pathological lymph nodes must have decreased to <10 mm in short axis. PR= At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.	First dosing date to date of confirmed disease progression, assessed up to 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Response (TTR)	TTR is defined as the time from the first dose of study treatment to first objective response [complete response (CR) or partial response (PR)] in patients with CR or PR.	First dosing date to date of first objective response, assessed up to 24 months
Duration of Response (DOR)	DOR is defined as the time from the first objective response (CR or PR) to documented disease progression in patients with CR or PR.	Date of first objective response to date of confirmed disease progression, assessed up to 24 months
Progression-Free Survival (PFS)	PFS is defined as the time from the first dose of study treatment to documented disease progression or death due to any cause.	First dosing to date to confirmed disease progression or death, assessed up to 48 months
Changes from baseline in thyroid stimulating hormone (TSH)	If TSH result is abnormal, subsequent testing of Free T3 and free T4 required.	Pre-treatment (within 7 days of first dose) to date of confirmed disease progression, assessed up to 24 months
Changes from baseline in electrocardiograms (ECGs)	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.	Screening to date of confirmed disease progression, assessed up to 24 months
Changes from baseline in Eastern Cooperative Oncology Group (ECOG) performance	ECOG performance status describes the level of impact that disease has on the patient's daily living abilities. Scale ranges from 0 (Fully active and able to carry on all pre-disease performance without restriction) to 5 (Dead).	Screening to date of confirmed disease progression, assessed up to 24 months
Population Pharmacokinetics (PK) of IPI-549-01	IPI-549 blood concentrations in ng/mL.	Pre-dose, 0.5, 1.5, 3 and 6 hours following administration on Day 1 of Cycles 1 and 2 (each cycle is 28 days)
Pharmacokinetics (PK) of Nivolumab	Nivolumab blood concentrations will be assayed in ug/mL.	Pre-infusion and within 2 minutes of end of infusion on Day 1 of Cycles 1 and 4; Pre-infusion on Day 1 of Cycles 2 and 3, and every 4 cycles starting at Cycle 5 (each cycle is 28 days)
Changes from baseline in pulse rate	Pulse rate as measured in beats per minute (bpm)	Screening to date of confirmed disease progression, assessed up to 24 months
Changes from baseline in temperature	Temperature as measured in celsius.	Screening to date of confirmed disease progression, assessed up to 24 months
Changes from baseline in respiration rate	Respiration rate as measured in breaths per minute.	Screening to date of confirmed disease progression, assessed up to 24 months
Changes from baseline in blood pressure	Systolic and diastolic blood pressure as measured in mmHg.	Screening to date of confirmed disease progression, assessed up to 24 months

Collaborators and Investigators

• Sponsor: Infinity Pharmaceuticals, Inc.
• Collaborators: Bristol-Myers Squibb
• Investigators: Study Director: Halle Zhang, PhD, RN, Infinity Pharmaceuticals, Inc.

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): September 25, 2019
• Primary Completion (Actual): November 30, 2020
• Study Completion (Actual): November 15, 2022

Study Registration Dates

• First Submitted: April 22, 2019
• First Submitted That Met QC Criteria: June 6, 2019
• First Posted (Actual): June 10, 2019

Study Record Updates

• Last Update Posted (Actual): November 25, 2022
• Last Update Submitted That Met QC Criteria: November 22, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: eganelisib; IPI-549
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Carcinoma; Carcinoma, Transitional Cell; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Nivolumab
• Other Study ID Numbers: IPI-549-02

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No