Clinical Trials /

A Dose-Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of IPI-549

NCT02637531

Description:

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.

Related Conditions:
  • Breast Carcinoma
  • Carcinoma
  • Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Dose-Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of IPI-549
  • Official Title: A Phase 1/1b First-In-Human, Dose-Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of IPI-549 Monotherapy and in Combination With Nivolumab in Subjects With Advanced Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: IPI-549-01
  • NCT ID: NCT02637531

Conditions

  • Advanced Solid Tumors (Part A/B/C/D)
  • Non-small Cell Lung Cancer (Part E)
  • Melanoma (Part E)
  • Squamous Cell Cancer of the Head and Neck (Part E)

Interventions

DrugSynonymsArms
IPI-549Part A/B: IPI-549 Dose Escalation
NivolumabOPDIVOPart C: IPI-549 and nivolumab

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Part A/B: IPI-549 Dose EscalationExperimentalParticipants receive IPI-549 orally (PO) once a day (QD) for Part A and twice a day (BID) in Part B until disease progression.
  • IPI-549
Part C: IPI-549 and nivolumabExperimentalParticipants receive IPI-549 (dose determined from Part A/B) orally in combination with nivolumab IV infusion (240 mg) every 2 weeks.
  • IPI-549
  • Nivolumab
Part D: IPI-549 MonotherapyExperimentalParticipants receive IPI-549 (dose determined from Part A/B) orally until disease progression.
  • IPI-549
Part D Annex: IPI-549 and nivolumabExperimentalParticipants receive IPI-549 (dose determined from Part A/B/C) orally in combination with nivolumab IV infusion (240 mg) every 2 weeks.
  • IPI-549
  • Nivolumab
Part E: NSCLC: IPI-549 and nivolumabExperimentalParticipants with NSCLC receive IPI-549 (dose determined from Part A/B/C) orally in combination with nivolumab IV infusion (240 mg) every 2 weeks.
  • IPI-549
  • Nivolumab
Part E: Melanoma: IPI-549 and nivolumabExperimentalParticipants with melanoma receive IPI-549 (dose determined from Part A/B/C) orally in combination with nivolumab IV infusion (240 mg) every 2 weeks.
  • IPI-549
  • Nivolumab
Part E: SCCHN: IPI-549 and nivolumabExperimentalParticipants with squamous cell cancer of the head and neck receive IPI-549 (dose determined from Part A/B/C) orally in combination with nivolumab IV infusion (240 mg) every 2 weeks.
  • IPI-549
  • Nivolumab

Eligibility Criteria

        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 or E 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

        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/exclusion criteria are met

          -  Administration of a live vaccine within 6 weeks of first dose of study drug

          -  Administration of any of the following within 1 week prior to the administration of
             study drug:

               -  Strong inhibitors or inducers of CYP3A4, including grapefruit products and
                  herbal supplements

               -  P-glycoprotein (P-gp) inhibitors

               -  Warfarin, phenytoin, or other substrates of CYP2C8 or CYP2C9 with a narrow
                  therapeutic range

               -  Medications associated with QTc interval prolongation or Torsades de Pointes

          -  Baseline QT interval corrected with Fridericia's method (QTcF) > 480 ms (average of
             triplicate readings) NOTE: criterion does not apply to subjects with a right or left
             bundle branch block

          -  Parts C, D-Annex, and E only: Subjects with active, known, or suspected autoimmune
             disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism
             due to autoimmune condition only requiring hormone replacement, psoriasis not
             requiring systemic treatment, or conditions not expected to recur in the absence of
             an external trigger are permitted to enroll

          -  Prior surgery or gastrointestinal dysfunction that may affect drug absorption (eg,
             gastric bypass surgery, gastrectomy)

          -  Concurrent active malignancy other than non-melanoma skin cancer, carcinoma in situ
             of the cervix, or prostate intraepithelial neoplasia

          -  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

          -  History of peptic ulcer and/or gastrointestinal bleed

          -  History of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia
             requiring medication or mechanical control within the last 6 months prior to
             Screening

          -  Unstable or severe uncontrolled medical condition (eg, unstable cardiac function,
             unstable pulmonary condition including pneumonitis and/or interstitial lung disease,
             uncontrolled diabetes) or any important medical illness or abnormal laboratory
             finding that would, in the Investigator's judgment, increase the risk to the subject
             associated with his or her participation in the study.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Part A/B/C: Dose Limiting Toxicities (DLT)
Time Frame:From date of initial dose until up to 28 days for IPI-549
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Part A/B: Adverse Events (AE) and safety laboratory values
Time Frame: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
Safety Issue:
Description:
Measure:Part A/B: Plasma concentrations of IPI-549 (metabolites, as appropriate)
Time Frame:Assessed during Days 1- 22 of Cycles 1 and 2, Assessed During Day 1 of Cycles 3 and 4
Safety Issue:
Description:
Measure:Part A/B: Overall response rate (ORR), complete response/remission (CR) or partial response/remission (PR)
Time Frame:Responses Assessed in Cycle 3 and every odd cycle through study completion, an average of 1 year
Safety Issue:
Description:
Measure:Part A/B: Duration of response (DoR)
Time Frame:Responses Assessed in Cycle 3 and every odd cycle through study completion, an average of 1 year
Safety Issue:
Description:
Measure:Part C: Adverse Events (AE) and safety laboratory values
Time Frame: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
Safety Issue:
Description:
Measure:Part C: Plasma concentrations of IPI-549 (metabolites as appropriate)
Time Frame:Assessed during Days 1- 2 of Cycles 1 and 2
Safety Issue:
Description:
Measure:Part C: Overall Response Rate (ORR)
Time Frame:Responses Assessed in Cycle 3 and every odd cycle through study completion, an average of 1 year
Safety Issue:
Description:
Measure:Part C: Duration of Response (DoR)
Time Frame:Responses Assessed in Cycle 3 and every odd cycle through study completion, an average of 1 year
Safety Issue:
Description:
Measure:Part D: Overall Response Rate (ORR)
Time Frame:Responses Assessed in Cycle 3 and every odd cycle through study completion, an average of 1 year
Safety Issue:
Description:
Measure:Part D: Duration of Response (DoR)
Time Frame:Responses Assessed in Cycle 3 and every odd cycle through study completion, an average of 1 year
Safety Issue:
Description:
Measure:Part D: Progression-Free Survival (PFS)
Time Frame:Responses Assessed in Cycle 3 and every odd cycle through study completion, an average of 1 year
Safety Issue:
Description:
Measure:Part D: Overall Survival (OS)
Time Frame:Estimated to be 3 years
Safety Issue:
Description:
Measure:Part D: Plasma concentrations of IPI-549 (and metabolites, as appropriate)
Time Frame:Assessed during Days 1- 15 of Cycles 1 and 2, Assessed During Day 1 of Cycles 3 and 4
Safety Issue:
Description:
Measure:Part E:Overall Response Rate (ORR)
Time Frame:Responses Assessed in Cycle 3 and every odd cycle through study completion, an average of 1 year
Safety Issue:
Description:
Measure:Part E: Duration of Response (DoR)
Time Frame:Responses Assessed in Cycle 3 and every odd cycle through study completion, an average of 1 year
Safety Issue:
Description:
Measure:Part E: Progression Free Survival (PFS)
Time Frame:Responses Assessed in Cycle 3 and every odd cycle through study completion, an average of 1 year
Safety Issue:
Description:
Measure:Part E: Overall Survival (OS)
Time Frame:Estimated to be 3 years
Safety Issue:
Description:
Measure:Part E: Plasma concentrations of IPI-549 (and metabolites, as appropriate)
Time Frame:Assessed during Days 1- 2 of Cycles 1 and 2
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Infinity Pharmaceuticals, Inc.

Trial Keywords

  • IPI-549
  • Phase 1
  • Advanced Solid Tumor
  • Non-small cell lung cancer
  • Melanoma
  • PI3K
  • Squamous Cell Cancer of the Head and Neck

Last Updated

March 2, 2017