Working…
COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC: https://www.coronavirus.gov.

Get the latest research information from NIH: https://www.nih.gov/coronavirus.
ClinicalTrials.gov
ClinicalTrials.gov Menu

Study of ARRY-614 Plus Either Nivolumab or Ipilimumab

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04074967
Recruitment Status : Recruiting
First Posted : August 30, 2019
Last Update Posted : June 25, 2020
Sponsor:
Collaborator:
Array BioPharma
Information provided by (Responsible Party):
Jason J. Luke, MD, University of Pittsburgh

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 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.

Condition or disease Intervention/treatment Phase
Renal Cell Carcinoma Melanoma Solid Tumor Drug: Phase Ib ARRY-614 + nivolumab Drug: Phase Ib ARRY-614 + ipilimumab Drug: Phase II ARRY-614 + ipilimumab Drug: Phase II ARRY-614 + nivolumab (melanoma) Drug: Phase II ARRY-614 + nivolumab (RCC) Phase 1 Phase 2

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.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 144 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Phase lb: subjects with advanced solid tumors will receive ARRY-614 in combination with nivolumab; subjects with melanoma will receive ARRY-614 in combination with ipilimumab immunotherapy

Phase ll: Subjects with RCC will receive ARRY-614 combined with nivolumab. Subjects with melanoma will ARRY-614 combined with ipilimumab or nivolumab. Assignment of melanoma patients to either the ARRY-614 combination arm with ipilimumab or nivolumab is at the discretion of the investigator.

Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase Ib/II Study of ARRY-614 Plus Either Nivolumab or Ipilimumab in Advanced Melanoma, Renal Cell Carcinoma, and Solid Tumors
Estimated Study Start Date : June 19, 2020
Estimated Primary Completion Date : November 30, 2021
Estimated Study Completion Date : November 30, 2021


Arm Intervention/treatment
Experimental: Phase Ib ARRY-614 + nivolumab
Participants with advanced solid tumors will receive ARRY-614 in combination with nivolumab.
Drug: Phase Ib ARRY-614 + nivolumab
Participants with advanced solid tumors will take ARRY-614 continuously in 4-week cycles (± 3 days). Nivolumab will be dosed according to FDA-approved dosing schedule.

Experimental: Phase Ib ARRY-614 + ipilimumab
Participants with melanoma will received ARRY-614 in combination with ipilimumab.
Drug: Phase Ib ARRY-614 + ipilimumab
Participants with melanoma will take ARRY-614 continuously in 4-week cycles (± 3 days). Ipilimumab therapy will be dosed according to FDA-approved dosing schedule.

Experimental: Phase II ARRY-614 + ipilimumab
Participants with melanoma will receive ARRY-614 combined with ipilimumab.
Drug: Phase II ARRY-614 + ipilimumab
Subjects with melanoma will receive the recommended Phase II dose of ARRY-614 (to be determined) daily in 4-week cycles (± 3 days). Ipilimumab will be dosed according to FDA-approved dosing schedule.

Experimental: Phase II ARRY-614 + nivolumab (melanoma)
Participants with melanoma will receive ARRY-614 combined with nivolumab.
Drug: Phase II ARRY-614 + nivolumab (melanoma)
Subjects with melanoma will receive the 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.

Experimental: Phase II ARRY-614 + nivolumab (RCC)
Participants with RCC will receive ARRY-614 combined with nivolumab.
Drug: Phase II ARRY-614 + nivolumab (RCC)
Subjects with RCC will receive the 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.




Primary Outcome Measures :
  1. Participants Experiencing a Dose Limiting Toxicity (DLT) [ Time Frame: Up to 28 days (during first cycle of treatment) ]
    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).

  2. Objective Response [ Time Frame: Up to 48 months ]
    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 :
  1. Adverse Events related to Study Treatment [ Time Frame: Up to 48 months ]
    The occurrence (number and type) toxicity events in participants receiving ARRY-614 in combination with either nivolumab or ipilimumab immunotherapy.

  2. Overall Survival (OS) [ Time Frame: Up to 48 months ]
    The length of time from the start of treatment that diagnosed participants remain alive, until the time of death from any cause.

  3. Progression Free Survival (PRS) [ Time Frame: Up to 48 months ]
    The length of time from first dose of either drug until disease progression or death from any cause, whichever occurs first.

  4. Duration of Response [ Time Frame: Up to 48 months ]

    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.


  5. Response per irRECIST [ Time Frame: Up to 48 months ]
    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.

  6. 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 ]
    Plasma concentrations and PK for ARRY-614 and its metabolite potentially, including Maximum Plasma Concentration [Cmax].

  7. 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 ]
    Gene expression changes will be presented as either positive (+) or negative (-).

  8. 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 ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04074967


Contacts
Layout table for location contacts
Contact: Krystle Eaton, BSN 412-623-7957 mientkiewiczk@upmc.edu

Locations
Layout table for location information
United States, Pennsylvania
UPMC Hillman Cancer Center Recruiting
Pittsburgh, Pennsylvania, United States, 15232
Contact: Krystle Eaton, BSN    412-623-7957    mientkiewiczk@upmc.edu   
Sponsors and Collaborators
Jason J. Luke, MD
Array BioPharma
Investigators
Layout table for investigator information
Principal Investigator: Jason J Luke, MD, PhD UPMC Hillman Cancer Center
Layout table for additonal information
Responsible Party: Jason J. Luke, MD, Associate Professor of Medicine, University of Pittsburgh
ClinicalTrials.gov Identifier: NCT04074967    
Other Study ID Numbers: HCC 19-097
First Posted: August 30, 2019    Key Record Dates
Last Update Posted: June 25, 2020
Last Verified: June 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
Layout table for MeSH terms
Carcinoma
Melanoma
Carcinoma, Renal Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms, Nerve Tissue
Nevi and Melanomas
Adenocarcinoma
Kidney Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Kidney Diseases
Urologic Diseases
Nivolumab
Ipilimumab
Antineoplastic Agents, Immunological
Antineoplastic Agents