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Study of ARRY-614 Plus Either Nivolumab or Nivolumab+Ipilimumab

Primary Purpose

Renal Cell Carcinoma, Melanoma, Solid Tumor

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Phase Ib ARRY-614 + nivolumab
Phase Ib ARRY-614 + nivolumab+ipilimumab
Phase II ARRY-614 + nivolumab
Phase II ARRY-614 + nivolumab+ipilimumab (melanoma)
Phase II ARRY-614 + nivolumab+ipilimumab (RCC)
Sponsored by
Jason J. Luke, MD
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Renal Cell Carcinoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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: nivolumab and ipilimumab must be available and appropriate for proposed 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.

Sites / Locations

  • UPMC Hillman Cancer CenterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

Phase Ib ARRY-614 + nivolumab

Phase Ib ARRY-614 + nivolumab + ipilimumab

Phase II ARRY-614 + nivolumab

Phase II ARRY-614 + nivolumab + ipilimumab (melanoma)

Phase II ARRY-614 + nivolumab + ipilimumab (RCC)

Arm Description

Participants with advanced solid tumors will receive ARRY-614 in combination with nivolumab. (histologically confirmed metastatic or unresectable malignancy with lacking curative measures; nivolumab must be available and appropriate for proposed therapy)

Participants with advanced solid tumors will received ARRY-614 in combination with nivolumab + ipilimumab. (histologically confirmed metastatic or unresectable malignancy with lacking curative measures; nivolumab and ipilimumab must be available and appropriate for proposed therapy)

Participants with of NSCLC and HNSCCC will receive ARRY-614 combined with nivolumab.

Participants with melanoma will receive ARRY-614 combined with nivolumab + ipilimumab.

Participants with RCC will receive ARRY-614 combined with nivolumab + ipilimumab.

Outcomes

Primary Outcome Measures

Participants Experiencing a Dose Limiting Toxicity (DLT)
Safety and recommended Phase ll dose of ARRY-614 in combination with either nivolumab or or nivolumab+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).
Objective Response
The probability of (objective) response to treatment (estimation). 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.

Secondary Outcome Measures

Adverse Events related to Study Treatment
The occurrence (number and type) of toxicity events in participants receiving ARRY-614 in combination with either nivolumab or or nivolumab+ipilimumab immunotherapy. Adverse Events and Serious Adverse Events per CTCAE v5.0 at least Possibly Related to Treatment at (Phase II dose).
Overall Survival (OS)
The length of time from the start of treatment that diagnosed participants remain alive, until the time of death from any cause.
Progression Free Survival (PRS)
The length of time from first dose of either drug until disease progression or death from any cause, whichever occurs first.Per RECIST v1.1: 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.
Duration of Response
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.
Response per Immune-related response criteria (irRECIST)
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.

Full Information

First Posted
August 19, 2019
Last Updated
March 26, 2023
Sponsor
Jason J. Luke, MD
Collaborators
Array BioPharma
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1. Study Identification

Unique Protocol Identification Number
NCT04074967
Brief Title
Study of ARRY-614 Plus Either Nivolumab or Nivolumab+Ipilimumab
Official Title
A Phase Ib/II Study of ARRY-614 Plus Either Nivolumab or Nivolumab+Ipilimumab in Advanced Solid Tumors
Study Type
Interventional

2. Study Status

Record Verification Date
March 2023
Overall Recruitment Status
Recruiting
Study Start Date
June 11, 2020 (Actual)
Primary Completion Date
March 2026 (Anticipated)
Study Completion Date
June 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Jason J. Luke, MD
Collaborators
Array BioPharma

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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 nivolumab+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 ARRY-614 + nivolumab+ipilimumab immunotherapy in patients with with NSCLC, HNSCC, melanoma and RCC and melanoma.
Detailed Description
This phase Ib/II study of PO administered ARRY-614 in combination with checkpoint immunotherapy. In phase Ib, this includes ARRY-614 plus nivolumab or ARRY-614 + nivolumab+ipilimumab in patients with selected advanced solid tumors. In phase II, this includes ARRY-614 in combination with nivolumab in a combined cohort of NSCLC and HNSCCC as well as two arms with patients having either melanoma and RCC, where ARRY-614 will be combined with nivolumab+ipilimumab. The objective of the Ib phase is to determine the safety, tolerability and recommended phase II dose of ARRY-614 with either nivolumab or nivolumab+ipilimumab combination therapy. The objective of Phase II is to determine best ORR in the three separate phase II arms: ARRY-614 plus nivolumab+ipilimumab in melanoma or RCC as well as ARRY-614 plus nivolumab in a combined cohort of NSCLC and HNSCC. The recommended phase II dose will be informed by the phase Ib safety study of ARRY-614, the plasma PK of ARRY-614 and the metabolite, AR00451575, and the PD effects of ARRY-614 in pre and post dose peripheral blood samples. In phase Ib, trial participants will take ARRY-614 continuously in 3- or 4-week cycles (± 3 days). Nivolumab and nivolumab+ipilimumab therapy will be dosed according to FDA-approved or compendium supported dosing schedule. In phase II, a similar dosing schedule will be pursued once the recommended phase II dose of ARRY-614 has been determined with nivolumab or nivolumab +ipilimumab. ARRY-614 will be given on a daily PO schedule in 3- or 4-week cycles (± 3 days).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Renal Cell Carcinoma, Melanoma, Solid Tumor, Non-small Cell Lung Cancer, Head and Neck Squamous Cell Carcinoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Model Description
Phase lb: subjects with advanced solid tumors will receive ARRY-614 in combination with nivolumab or ARRY-614 in combination with nivolumab + ipilimumab immunotherapy. Phase ll: Subjects with NSCLC or HNSCC will receive ARRY-614 combined with nivolumab. Subjects with melanoma will receive ARRY-614 combined with nivolumab + ipilimumab. Subjects with RCC will receive ARRY-614 combined with nivolumab + ipilimumab.
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
144 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Phase Ib ARRY-614 + nivolumab
Arm Type
Experimental
Arm Description
Participants with advanced solid tumors will receive ARRY-614 in combination with nivolumab. (histologically confirmed metastatic or unresectable malignancy with lacking curative measures; nivolumab must be available and appropriate for proposed therapy)
Arm Title
Phase Ib ARRY-614 + nivolumab + ipilimumab
Arm Type
Experimental
Arm Description
Participants with advanced solid tumors will received ARRY-614 in combination with nivolumab + ipilimumab. (histologically confirmed metastatic or unresectable malignancy with lacking curative measures; nivolumab and ipilimumab must be available and appropriate for proposed therapy)
Arm Title
Phase II ARRY-614 + nivolumab
Arm Type
Experimental
Arm Description
Participants with of NSCLC and HNSCCC will receive ARRY-614 combined with nivolumab.
Arm Title
Phase II ARRY-614 + nivolumab + ipilimumab (melanoma)
Arm Type
Experimental
Arm Description
Participants with melanoma will receive ARRY-614 combined with nivolumab + ipilimumab.
Arm Title
Phase II ARRY-614 + nivolumab + ipilimumab (RCC)
Arm Type
Experimental
Arm Description
Participants with RCC will receive ARRY-614 combined with nivolumab + ipilimumab.
Intervention Type
Drug
Intervention Name(s)
Phase Ib ARRY-614 + nivolumab
Intervention Description
ARRY-614 continuously in 4-week cycles (± 3 days). Nivolumab will be dosed according to FDA-approved dosing schedule.
Intervention Type
Drug
Intervention Name(s)
Phase Ib ARRY-614 + nivolumab+ipilimumab
Intervention Description
ARRY-614 continuously in 4-week cycles (± 3 days). Nivolumab will be dosed according to FDA-approved dosing schedule. Ipilimumab therapy will be dosed according to FDA-approved dosing schedule.
Intervention Type
Drug
Intervention Name(s)
Phase II ARRY-614 + nivolumab
Intervention Description
Recommended Phase II dose of ARRY-614 (to be determined) daily in 4-week cycles (± 3 days). Nivolumab will be dosed according to FDA-approved dosing schedule.
Intervention Type
Drug
Intervention Name(s)
Phase II ARRY-614 + nivolumab+ipilimumab (melanoma)
Intervention Description
Recommended Phase II dose of ARRY-614 (to be determined) daily in 4-week cycles (± 3 days). Nivolumab will be dosed according to FDA-approved dosing schedule. Ipilimumab therapy will be dosed according to FDA-approved dosing schedule.
Intervention Type
Drug
Intervention Name(s)
Phase II ARRY-614 + nivolumab+ipilimumab (RCC)
Intervention Description
Recommended Phase II dose of ARRY-614 (to be determined) daily in 4-week cycles (± 3 days). Nivolumab will be dosed according to FDA-approved dosing schedule. Ipilimumab therapy will be dosed according to FDA-approved dosing schedule.
Primary Outcome Measure Information:
Title
Participants Experiencing a Dose Limiting Toxicity (DLT)
Description
Safety and recommended Phase ll dose of ARRY-614 in combination with either nivolumab or or nivolumab+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).
Time Frame
Up to 28 days (during first cycle of treatment)
Title
Objective Response
Description
The probability of (objective) response to treatment (estimation). 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.
Time Frame
Up to 48 months
Secondary Outcome Measure Information:
Title
Adverse Events related to Study Treatment
Description
The occurrence (number and type) of toxicity events in participants receiving ARRY-614 in combination with either nivolumab or or nivolumab+ipilimumab immunotherapy. Adverse Events and Serious Adverse Events per CTCAE v5.0 at least Possibly Related to Treatment at (Phase II dose).
Time Frame
Up to 48 months
Title
Overall Survival (OS)
Description
The length of time from the start of treatment that diagnosed participants remain alive, until the time of death from any cause.
Time Frame
Up to 48 months
Title
Progression Free Survival (PRS)
Description
The length of time from first dose of either drug until disease progression or death from any cause, whichever occurs first.Per RECIST v1.1: 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.
Time Frame
Up to 48 months
Title
Duration of Response
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.
Time Frame
Up to 48 months
Title
Response per Immune-related response criteria (irRECIST)
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.
Time Frame
Up to 48 months
Other Pre-specified Outcome Measures:
Title
Pharmacokinetic profile of ARRY-614
Description
Plasma concentrations and PK for ARRY-614 and its metabolite potentially, including Maximum Plasma Concentration [Cmax].
Time Frame
Day 1 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
Title
Tumor Inflammation Signature (TIS) score
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.
Time Frame
28 days prior to treatment, Day 1 of Cycle 1, Cycle 2 and subsequent cycles (28 day cycles); up to 3 months
Title
Pharmacodynamic profile of ARRY-614
Description
Gene expression changes will be presented as either positive (+) or negative (-).
Time Frame
28 days prior to treatment, Days 1 and 15 of Cycles 1 and 2, and Day 1 of Cycle 3; up to 3 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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 curative measures do not exist or are no longer effective. a.Trial participants must have nivolumab or ipilimumab therapy available and must be appropriate for this therapy. For Phase II: Participants with melanoma who previously experienced disease progression on anti-PD1 (with or without ipilimumab). Participants with RCC who previously experienced disease progression on anti-PD1 (with or without ipilimumab). Participants with NSCLC or HNSCC who previously experienced disease progression on anti-PD1 (with or without ipilimumab). Progression on prior anti-PD1/L1 or anti-PD1/anti-CTLA4 antibodies must meet definitions for primary or secondary resistance and regrowth after stopping therapy as below or there must be documentation by the treating investigator of rapid disease progression such that these criteria cannot be assessed (suggestions from the Society for ImmunoTherapy of Cancer PD1 Resistance Working Group). 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: Absolute neutrophil count ≥1,500/mm3 or 1.5 ×109/L Hemoglobin ≥8 g/dL Platelets ≥100,000/mm3 or 100 × 109/L Have adequate hepatic function as evidenced by: Serum total bilirubin ≤2 × upper limit of normal (ULN), unless considered due to Gilbert's disease 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: A stable regimen of highly active anti-retroviral therapy (HAART) No requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infections 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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Julie Urban, PhD
Phone
412-623-7396
Email
urbanj2@upmc.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Amy Rose, RN
Phone
412-647-8587
Email
kennaj@upmc.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jason J Luke, MD, PhD
Organizational Affiliation
UPMC Hillman Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
UPMC Hillman Cancer Center
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15232
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Julie Urban, PhD
Phone
412-623-7396
Email
urbanj2@upmc.ed
First Name & Middle Initial & Last Name & Degree
Amy Rose, RN
Phone
412-647-8587
Email
kennaj@upmc.edu
First Name & Middle Initial & Last Name & Degree
Jason J Luke, MD

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

Study of ARRY-614 Plus Either Nivolumab or Nivolumab+Ipilimumab

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