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.
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
- 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
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
2. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5x the
institutional ULN or ≤ 5.0x institutional ULN in the presence of known liver
- 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
- 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
- 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
- Underwent major surgery within 4 weeks of Day 1 or have not recovered from
- 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