Clinical Trials /

Study of ARRY-614 Plus Either Nivolumab or Ipilimumab

NCT04074967

Description:

In this study, the Phase Ib portion aims to establish safety and tolerability of ARRY-614 with either nivolumab or ipilimumab and to determine a recommended phase II dose of ARRY-614 in combination with either nivolumab or ipilimumab immunotherapy in patients with selected advanced solid tumors. The Phase II portion will estimate the efficacy of ARRY-614 in combination with either nivolumab or ipilimumab immunotherapy in patients with melanoma and renal cell carcinoma.

Related Conditions:
  • Malignant Solid Tumor
  • Melanoma
  • Renal Cell Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of ARRY-614 Plus Either Nivolumab or Ipilimumab
  • Official Title: A Phase Ib/II Study of ARRY-614 Plus Either Nivolumab or Ipilimumab in Advanced Melanoma, Renal Cell Carcinoma, and Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: HCC 19-097
  • NCT ID: NCT04074967

Conditions

  • Renal Cell Carcinoma
  • Melanoma
  • Solid Tumor

Interventions

DrugSynonymsArms
Phase Ib ARRY-614 + nivolumabPhase Ib ARRY-614 + nivolumab
Phase Ib ARRY-614 + ipilimumabPhase Ib ARRY-614 + ipilimumab
Phase II ARRY-614 + ipilimumabPhase II ARRY-614 + ipilimumab
Phase II ARRY-614 + nivolumab (melanoma)Phase II ARRY-614 + nivolumab (melanoma)
Phase II ARRY-614 + nivolumab (RCC)Phase II ARRY-614 + nivolumab (RCC)

Purpose

In this study, the Phase Ib portion aims to establish safety and tolerability of ARRY-614 with either nivolumab or ipilimumab and to determine a recommended phase II dose of ARRY-614 in combination with either nivolumab or ipilimumab immunotherapy in patients with selected advanced solid tumors. The Phase II portion will estimate the efficacy of ARRY-614 in combination with either nivolumab or ipilimumab immunotherapy in patients with melanoma and renal cell carcinoma.

Detailed Description

      In the Phase lb portion of the trial: Participants must have a histologically confirmed
      malignancy that is metastatic or unresectable for which standard curative or palliative
      measures do not exist or are no longer effective. Melanoma trial participants must have
      either nivolumab or ipilimumab available and have progressed on anti-PD1 or
      anti-PD1/anti-CTLA4 combination therapy. Other advanced solid tumor trial participants must
      have nivolumab or therapy available and must be appropriate for this therapy. In the Phase ll
      portion of the trial: Participants with melanoma who previously experienced disease
      progression on anti-PD1 may enter the ARRY-614 plus nivolumab cohort or the ARRY-614 plus
      ipilimumab cohort. Participants with melanoma entering the ARRY-614 plus ipilimumab cohort
      must be naïve to ipilimumab therapy. Participants with RCC who previously experienced disease
      progression on anti-PD1 may enter the ARRY-614 plus nivolumab cohort. Potential participants
      will undergo Screening Procedures to determine eligibility within 28 days prior to the start
      of study treatment on Cycle 1, Day 1 (C1D1). Results of standard of care tests or
      examinations performed prior to obtaining informed consent and within 21 days prior to Cycle
      1 Day 1 may be used for screening assessments rather than repeating such tests. The first 5
      patients in each Phase II arm will undergo pre and on-treatment biopsies. The second biopsy
      will occur at C2D1 ± 7 days.Participants who meet all study eligibility criteria will be
      eligible to start study treatment. Patients will receive ARRY-614 on a QD continuous
      schedule. One cycle is defined as 4 weeks (28 days) ± 3 days. Prescribed QD doses should be
      taken at consistent times each day, as close to 24 ± 2 hours apart as possible. Daily study
      treatment will begin on C1D1 with planned concurrent dosing of ARRY-614 and either nivolumab
      or ipilimumab. Upon determination of the Recommend Phase ll Doseof ARRY-614, a similar dosing
      schedule will be pursued. Three simultaneous phase II, tumor-specific trials will be
      conducted: melanoma with nivolumab, melanoma with ipilimumab, and RCC with nivolumab.
      ARRY-614 will be given on a daily PO schedule in 4-week cycles (± 3 days). Nivolumab and
      ipilimumab will be given according to the corresponding FDA label dosing schedule for each
      individual agent.
    

Trial Arms

NameTypeDescriptionInterventions
Phase Ib ARRY-614 + nivolumabExperimentalParticipants with advanced solid tumors will receive ARRY-614 in combination with nivolumab.
  • Phase Ib ARRY-614 + nivolumab
Phase Ib ARRY-614 + ipilimumabExperimentalParticipants with melanoma will received ARRY-614 in combination with ipilimumab.
  • Phase Ib ARRY-614 + ipilimumab
Phase II ARRY-614 + ipilimumabExperimentalParticipants with melanoma will receive ARRY-614 combined with ipilimumab.
  • Phase II ARRY-614 + ipilimumab
Phase II ARRY-614 + nivolumab (melanoma)ExperimentalParticipants with melanoma will receive ARRY-614 combined with nivolumab.
  • Phase II ARRY-614 + nivolumab (melanoma)
Phase II ARRY-614 + nivolumab (RCC)ExperimentalParticipants with RCC will receive ARRY-614 combined with nivolumab.
  • Phase II ARRY-614 + nivolumab (RCC)

Eligibility Criteria

        Inclusion Criteria:

          -  Age ≥18 years.

          -  For Phase Ib: Trial participants must have a histologically confirmed malignancy that
             is metastatic or unresectable for which standard curative or palliative measures do
             not exist or are no longer effective.

               1. For melanoma: trial participants must have either nivolumab or ipilimumab
                  available and have progressed on anti-PD1 or anti-PD1/anti-CTLA4 combination
                  therapy.

               2. For advanced solid tumors: trial participants must have nivolumab or therapy
                  available and must be appropriate for this therapy.

          -  For Phase II:

               1. Participants with melanoma who previously experienced disease progression on
                  anti-PD1 may enter the ARRY-614 plus nivolumab cohort or the ARRY-614 plus
                  ipilimumab cohort. Participants with melanoma entering the ARRY-614 plus
                  ipilimumab cohort must be naïve to ipilimumab therapy.

               2. Participants with RCC who previously experienced disease progression on anti-PD1
                  may enter the ARRY-614 plus nivolumab cohort

          -  Have an ECOG PS score of 0 or 1 (Appendix 13.A).

          -  Have an expected survival of ≥3 months.

          -  Have at least one evaluable and measurable lesion as defined by RECIST v1.1.

          -  The first five patients in each Phase II cohort must have tumors determined to be
             easily accessible for biopsy and must be willing to have two biopsies

          -  Have recovered from toxicities associated with prior anticancer therapy to baseline or
             Grade 1 unless stabilized under medical management per investigator.

          -  Have adequate bone marrow function as evidenced by:

               1. Absolute neutrophil count ≥1,500/mm3 or 1.5 ×109/L

               2. Hemoglobin ≥8 g/dL

               3. Platelets ≥100,000/mm3 or 100 × 109/L

          -  Have adequate hepatic function as evidenced by:

               1. Serum total bilirubin ≤2 × upper limit of normal (ULN), unless considered due to
                  Gilbert's disease

               2. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5x the
                  institutional ULN or ≤ 5.0x institutional ULN in the presence of known liver
                  metastases.

          -  Patients with creatinine clearance > 30 mL/min, (measured using Cockcroft-Gault
             equation or the estimated glomerular filtration rate from the Modification of Diet in
             Renal Disease Study) are included in the study.

          -  Be able to understand and willing to sign the informed consent form (or have legal
             representation) and to comply with scheduled visits, treatment plans, procedures, and
             laboratory tests, including serial peripheral blood sampling, biopsies, and urine
             sampling, during the study. A legally authorized representative may consent on behalf
             of a subject who is otherwise unable to provide informed consent if acceptable to and
             approved by the site's IRB/Independent Ethics Committee (IEC).

          -  Female patients with reproductive potential must have a negative serum pregnancy test
             prior to the start of therapy, or a confirmation from an obstetrician in case of
             equivocal serum pregnancy results. Females of reproductive potential are defined as
             sexually mature women who have not undergone a hysterectomy, bilateral oophorectomy,
             or tubal occlusion or who have not been naturally postmenopausal (ie, who have not
             menstruated) for at least 24 consecutive months (ie, have not had menses at any time
             in the preceding 24 consecutive months). Women with reproductive potential, as well as
             fertile men and their partners who are female with reproductive potential, must agree
             to use two effective forms of contraception (including at least one barrier form) from
             the time of giving informed consent throughout the study and for 5 months after the
             last dose of therapy for women, and 7 months after last dose for men. Effective forms
             of contraception are defined as hormonal PO contraceptives, injectables, patches,
             intrauterine devices, intrauterine hormone-releasing systems, bilateral tubal
             ligation, condoms with spermicide, or male partner sterilization.

          -  Patients positive for human immunodeficiency virus (HIV) are NOT excluded from this
             study, but HIV-positive patients must have:

               1. A stable regimen of highly active anti-retroviral therapy (HAART)

               2. No requirement for concurrent antibiotics or antifungal agents for the prevention
                  of opportunistic infections

               3. A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standard
                  PCR-based test

        Exclusion Criteria:

          -  Received systemic anticancer therapy or an investigational agent <2 weeks prior to Day
             1 (washout from prior immune based anticancer therapy is 4 weeks). In addition, the
             first dose of study treatment should not occur before a period ≥5 half-lives of the
             investigational agent has elapsed (excluding nivolumab therapy or combination
             anti-PD1/ipilimumab combination therapy in RCC - prior ipilimumab not permitted in
             melanoma cohort).

          -  For ST, have underwent hepatic radiation, chemoembolization, and radiofrequency
             ablation <4 weeks prior to Day 1.

          -  Participants must not have had a prior anti-cancer monoclonal antibody (mAb) within 4
             weeks prior to study Day 1 (with exception of anti-PD1/ipilimumab combination therapy)
             or have not recovered (i.e. < Grade 1 at baseline) from adverse events due to agents
             administered more than 4 weeks earlier.

          -  Participants must not have a diagnosis of immunodeficiency or be receiving systemic
             steroid therapy at a dose of >10 mg prednisone daily or equivalent at time of first
             dose of trial treatment (this criterion does not apply to HIV-positive patients as
             detailed in the inclusion criteria).

          -  Participants must not have active autoimmune disease that has required systemic
             treatment in the past 2 years (i.e. with use of disease modifying agents,
             corticosteroids or immunosuppressive drugs). Replacement therapy (e.g. thyroxine,
             insulin, or physiologic corticosteroids replacement therapy for adrenal or pituitary
             insufficiency, etc.) is not considered a form of systemic treatment.

          -  Participants must not have a known history of non-infectious pneumonitis that required
             steroids for treatment.

          -  Participants must not have evidence of active interstitial lung disease.

          -  Have known symptomatic brain metastases requiring steroids. Patients with previously
             diagnosed brain metastases are eligible if they have completed their treatment and
             have recovered from the acute effects of radiation therapy or surgery prior to study
             entry, have discontinued corticosteroid treatment for these metastases for at least 1
             week and have radiographically stable disease for at least 1 month prior to study
             entry. Note: up to 10 mg per day of prednisone equivalent will be allowed.

          -  Have a history of another primary cancer that is active requiring treatment,
             progressing or for which the investigator believes will make disease assessment
             unreliable.

          -  Underwent major surgery within 4 weeks of Day 1 or have not recovered from
             post-surgery toxicities.

          -  Are pregnant or breastfeeding.

          -  Have an active infection requiring systemic anti-infective therapy or with an
             unexplained fever >38.5°C within 7 days of Day 1 (at the discretion of the
             Investigator, patients with tumor fever may be enrolled).

          -  Have any known hypersensitivity to any of the components of ARRY-614 or
             anti-PD1/ipilimumab combination therapies.

          -  Have significant active cardiac disease within 6 months prior to the start of study
             treatment, including New York Heart Association (NYHA) Class III or IV congestive
             heart failure); myocardial infarction; unstable angina; and/or stroke.

          -  Have known LVEF <40% by ECHO scan (or by other methods according to institutional
             practice) obtained within 28 days prior to the start of study treatment (testing is
             not otherwise mandatory).

          -  Have known active hepatitis B (HBV) or hepatitis C (HCV) infections. Patients with a
             sustained viral response to HCV treatment or immunity to prior HBV infection will be
             permitted. Patients with chronic HBV that is adequately suppressed per institutional
             practice will be permitted.

          -  Have any other acute or chronic medical or psychiatric condition, including recent
             (within 12 months of Day 1) or active suicidal ideation or behavior, or a laboratory
             abnormality that may increase the risk associated with study participation or
             investigational product administration or may interfere with the interpretation of
             study results and, in the judgment of the Investigator, would make the subject
             inappropriate for entry into this study.

          -  Have known active inflammatory gastrointestinal disease, chronic diarrhea, previous
             gastric resection or lap band dysphagia, short-gut syndrome, gastroparesis, or other
             conditions that limit the ingestion or gastrointestinal absorption of drugs
             administered PO. Gastroesophageal reflux disease under medical treatment is allowed
             (assuming no drug interaction potential).

          -  Have been committed to an institution by an order issued either by the judicial or
             administrative authorities.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Participants Experiencing a Dose Limiting Toxicity (DLT)
Time Frame:Up to 28 days (during first cycle of treatment)
Safety Issue:
Description:Safety and recommended Phase ll dose of ARRY-614 in combination with either nivolumab or ipilimumab per NCI Common Terminology Criteria for Adverse Events (CTCAE) v.5.0: Any AE (unless attributable to an extraneous cause, ex. disease progression) that satisfies ≥1 of the following: Grade 3 or 4 nausea or vomiting; Grade 3 or 4 nausea or vomiting despite anti emetic prophylaxis; Grade 3 or 4 diarrhea; Grade 3 or 4 diarrhea despite the administration of anti-diarrheals. Other Grade 3 or 4 (except asymptomatic amylase/lipase or other asymptomatic biochemical marker that does not resolve with adequate treatment in ≤1 week). Hematologic AEs: Absolute neutrophil count (ANC) <500/mm^3 for ≥5 days, Febrile neutropenia (ANC < 1,000/mm^3 and single temperature ≥38.3 °C or sustained temperature of ≥38.0 °C for ≥1 hour), Platelets <25,000/mm^3, Hemoglobin <8.0 g/dL, Grade 3 hemorrhage associated with thrombocytopenia < Grade 4 (i.e. Grade 3 hemorrhage with platelets >25,000/mm^3).

Secondary Outcome Measures

Measure:Adverse Events related to Study Treatment
Time Frame:Up to 48 months
Safety Issue:
Description:The occurrence (number and type) toxicity events in participants receiving ARRY-614 in combination with either nivolumab or ipilimumab immunotherapy.
Measure:Overall Survival (OS)
Time Frame:Up to 48 months
Safety Issue:
Description:The length of time from the start of treatment that diagnosed participants remain alive, until the time of death from any cause.
Measure:Progression Free Survival (PRS)
Time Frame:Up to 48 months
Safety Issue:
Description:The length of time from first dose of either drug until disease progression or death from any cause, whichever occurs first.
Measure:Duration of Response
Time Frame:Up to 48 months
Safety Issue:
Description:Time between the initial response to treatment per RECIST v1.1 and subsequent disease progression. Per RECIST v1.1: Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (target or non-target) with reduction in short axis to <10 mm. Partial Response (PR): ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Progressive Disease (PD):≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of ≥5 mm. The appearance ≥1 new lesion(s) is considered progression.
Measure:Response per irRECIST
Time Frame:Up to 48 months
Safety Issue:
Description:irCR (Complete Response):Disappearance of non-nodal lesions.All pathologic lymph nodes <10 mm (2 consecutive measures ≥4 weeks apart); irPR (Partial Response):≥30% decrease from baseline (2 consecutive measures ≥4 weeks apart); irPD (Progressive Disease):≥20% increase from nadir and ≥5mm (2 consecutive measures ≥4 weeks apart); irSD (Stable Disease): Not sufficient decrease for PR, nor sufficient increase for PD; irPR (Progressive Disease): Disappearance of all non-nodal lesions.All pathologic lymph nodes <10 mm (Non-Target Lesions:Any other than disappearance of all non-nodal lesions and reduction of pathologic lymph nodes <10 mm). Baseline tumor burden: sum of single diameters (short axis for nodal lesions, longest diameter for other lesions) for target lesions. In subsequent scans, the diameters of new measurable lesions are added to the tumor burden. Re-treatment: ≤5 target lesions (=/≠ original lesions) are selected and a new baseline tumor burden will be established.
Measure:Pharmacokinetic profile of ARRY-614
Time Frame:Day 1, 8 and 15 of Cycle 1, Day 1 and 15 of Cycle 2, and Day 1 of subsequent cycles (28 day cycles); up to 3 months
Safety Issue:
Description:Plasma concentrations and PK for ARRY-614 and its metabolite potentially, including Maximum Plasma Concentration [Cmax].
Measure:Pharmacodynamic profile of ARRY-614
Time Frame:28 days prior to treatment, Day 1 of Cycle 1, Cycle 2 and subsequent cycles (28 day cycles); up to 3 months
Safety Issue:
Description:Gene expression changes will be presented as either positive (+) or negative (-).
Measure:Tumor Inflammation Signature (TIS) score
Time Frame:28 days prior to treatment, Day 1 of Cycle 1, Cycle 2 and subsequent cycles (28 day cycles); up to 3 months
Safety Issue:
Description:The Tumor Inflammation Signature (TIS) is an investigational use only (IUO) 18-gene signature that measures a pre-existing but suppressed adaptive immune response within tumors using a gene expression algorithm. Higher TIS scores are associated with an increase in overall response rate and better prognosis.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Jason J. Luke, MD

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