Duvelisib in Combination With Nivolumab in Patients With Advanced Unresectable Melanoma

This trial is a Phase I/II study in which a combination of duvelisib and nivolumab will be used to treat a total of patients diagnosed with advanced unresectable melanoma who have progressed on anti-PD1 therapy. The Recommended Phase II Dose of oral duvelisib will be determined and administered with intravenous nivolumab 480mg for up to 1 year or until the patient's disease does not progress or the patient experiences unacceptable side effects to treatment.

This trial will study of PI3Kγδ inhibitor duvelisib in combination with nivolumab in patients with advanced unresectable melanoma who have progressed on anti-PD1 therapy. In the Phase I part of the study (18) patients will be administered nivolumab 480mg intravenously and duvelisib orally in doses from 15mg once a day to 25mg twice a day to determine the recommended dose for the Phase II part of the study. In the Phase II study patients will be administered nivolumab 480mg intravenously and duvelisib orally (dose not determined until the Phase 1 study is completed) up to 1 year as long as their disease doesn't progress or have unacceptable side effects to the study drugs. This trial will attempt to determine whether duvelisib acts as an immunomodulator, to shift the TME from an immunosuppressive to an immunostimulatory setting, to overcome acquired resistance in anti-PD1 treated patients. The phase I portion of the study is uniquely designed to find the ideal dose of duvelisib as an immunomodulator, which is suspected to be lower than the previously determined maximum tolerated dose (MTD) of duvelisib in lymphoma studies.

Eligibility Criteria:
Inclusion Criteria:

* AJCC 8th edition criteria for unresectable stage IIIB, stage IIIC, stage IIID or stage IV melanoma who have received at least 3 months of prior treatment with an anti-PD1 or anti-PDL1 antibody and who have progressed on this treatment. Patients who have received a combination anti-PD1 and anti-CTLA4 therapy who exhibit progression at this interval are also permitted. There are no restrictions regarding time since last anti-PD1 treatment, or number of therapies after anti-PD1.
* Age ≥ 18 years
* ECOG performance status ≤ 2 or Karnofsky ≥ 60%
* Patients must have normal organ and bone marrow function as defined below:

  * Hemoglobin ≥9.0 g/dL
  * Absolute neutrophil count ≥1500 cells/µL
  * Platelets ≥100,000 cells/µL
  * Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN). Patients with Gilbert's syndrome must have normal direct bilirubin
  * AST/ALT ≤2.5x ULN in subjects with liver metastasis, must be within normal limits for those without liver metastasis
  * Creatinine \< 1.5 mg/dL
* For patients with actionable BRAF mutations, treatment with BRAF and MEK inhibitors prior to initiation on trial is recommended, unless patients are intolerant of therapy or choose not to pursue BRAF targeted therapy.
* Patients must have measurable disease, defined as at least one tumor lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥10mm with CT scan, MRI or by calipers if documented on clinical exam. If patients have a single lesion, the lesion must be amenable to biopsy without interfering with radiographic assessment as determined by one of the co-PIs.
* Duvelisib and nivolumab therapy may be harmful for a developing fetus. Women of child bearing potential (WCBP) must have a negative urine or serum β human chorionic gonadotropin (βhCG) pregnancy test within 7 days before starting treatment. WCBP and men must agree to use highly effective contraception (pharmacologic birth control, barrier methods or abstinence) prior to study entry and for the duration of study participation through 5 months after the last dose of study medication. Should a woman become pregnant while she or her partner are participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use highly effective contraception prior to the study, for the duration of study participation and 12 weeks following the last dose.
* WCBP defined as a sexually mature woman who as not undergone surgical sterilization or who has not been naturally postmenopausal for at least 12 consecutive months for women \>55 years of age
* Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria

* Patients with known or suspected CNS metastases with are excluded, unless the following criteria are met:

  * Subjects have controlled brain metastasis, defined as metastases without radiographic progression for at least 4 weeks following treatment with stereotactic radiation and/or surgical treatment at the time of randomization
  * Subjects must be off steroids without symptoms of CNS disease for at least 2 weeks prior to treatment
  * Subjects with signs or symptoms of brain metastasis are not eligible unless brain metastasis is ruled out by computed tomography or magnetic resonance imaging
* Patients with uveal or mucosal melanoma are excluded
* Subjects with an active, known or suspected autoimmune disease. Subjects with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders such as vitiligo, alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll
* Subjects with history of chronic liver disease, veno-occlusive disease, active alcohol abuse or illicit drug use other than marijuana or its derivatives
* Uncontrolled or significant cardiovascular disease including but not limited to the following:

  * Myocardial infarction (MI) or stroke/transient ischemic attack (TIA) within the 6 months prior to consent
  * Uncontrolled angina within the 3 months prior to consent
  * Any history of clinically significant arrhythmias (such as ventricular tachycardia, ventricular fibrillation, torsades de pointes, or poorly controlled atrial fibrillation)
  * History of other clinically significant cardiovascular disease (i.e., cardiomyopathy, congestive heart failure with New York Heart Association \[NYHA\] functional classification III-IV, pericarditis, significant pericardial effusion, significant coronary stent occlusion, poorly controlled deep venous thrombosis, etc)
  * Cardiovascular disease-related requirement for daily supplemental oxygen
  * Subjects with history of myocarditis, regardless of etiology
  * Baseline left ventricular ejection fraction (LVEF) \<45%. ECHO/MUGA not required at screening unless history of significant cardiac history.
  * QTc prolongation \> 500 msec
* Uncontrolled or significant pulmonary disease including but not limited to the following:

  * Obstructive or restrictive lung disease requiring home oxygen
  * Hospitalization with chronic obstructive pulmonary disease (COPD) exacerbation within the last 6 months
  * History or concurrent condition of interstitial lung disease of any severity
  * Prior history of pneumonitis of grade II or higher, regardless of cause
  * Patients with diagnosis of obstructive sleep apnea (OSA) who are compliant with prescribed therapy (nocturnal O2, CPAP or BiPAP) are allowed on study
* Uncontrolled or significant infectious disease including but not limited to the following:

  * Ongoing treatment for systemic bacterial, fungal or viral infection at screening
  * Subjects are not excluded for antimicrobial, antifungal or antiviral prophylaxis if other inclusion/exclusion criteria are met
  * Active cytomegalovirus (CMV) or Epstein-Barr virus (EBV) infection (i.e., subjects with known history of detectable viral load)
  * Infection with hepatitis B, hepatitis C, human immunodeficiency virus (HIV), or human T-lymphotropic virus type 1
  * Subjects with a positive hepatitis B surface antigen \[HBsAg\] or hepatitis C antibody \[HCV Ab\] will be excluded, unless documented treatment and resolution of hepatitis C treatment Subjects with a positive hepatitis B core antibody (HBcAb) must have negative hepatitis B virus (HBV) deoxyribonucleic acid (DNA) assay to be eligible, must receive prophylaxis with entecavir (or equivalent) concomitant with duvelisib treatment, and must be periodically monitored for HBV reactivation by institutional guidelines. If unable to receive prophylaxis, then case will be discussed with investigators to determine eligibility.
  * History of tuberculosis treatment within 2 years prior to enrollment
* Patients with history of encephalitis, meningitis, or uncontrolled seizures in the year prior to informed consent
* Ongoing chronic treatment with immunosuppressants (e.g. cyclosporine) or systemic steroids \> 10mg of prednisone or equivalent once daily. Topical and inhaled steroids are allowed.
* Subjects with other uncontrolled medical conditions or other illnesses, laboratory findings or other factors that would, in the investigator's judgment, increase the risk to the subject associated with his or her participation in the study.
* Patients who are receiving other investigational therapies will be excluded
* Patients who had a history of life-threatening toxicity related to prior immune therapy (e.g. anti-CTLA-4, anti-PD1 or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways) except those that are well controlled an unlikely to be an issue with standard countermeasures (e.g. endocrine disorders managed by hormone replacement).
* Subjects with a history of grade II or greater immune-mediated colitis. Patients whose toxicity was clearly attributable to anti-CTLA-4 treatment (tolerated anti-PD1 after receiving anti-CTLA4) may still be allowed on trial.
* Subjects with a history of grade II or greater pneumonitis or transaminitis.
* Prior treatments with PI3K inhibitors
* Subject has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone therapy with curative intent, or treated in situ cervical cancer for which there is appropriate ongoing surveillance
* Subject had therapy with radiation, surgery or chemotherapy within 4 weeks prior to time of consent and/or has not recovered from adverse events to due to prior therapy. Subjects should be adequately recovered from all toxicities, complications, or acute illnesses prior to starting investigational therapy.
* A maximum of three patients who have received talimogene laherparepvec (T-vec) as prior therapy will be allowed to enroll in the Phase II portion of the study. However, study-related biopsies must be performed at a disease site that was not injected with T-vec or adjacent to a T-vec injection site.
* Subjects who are unable or unwilling to take prophylaxis for Pneumocystis jirovecii, human simplex virus (HSV) or herpes zoster (VZV) at time of screening
* Subjects with known hypersensitivity to duvelisib and/or its excipients: Microcrystalline cellulose and magnesium stearate
* Prisoners or subjects who are involuntarily incarcerated
* Subjects who are compulsorily detained for treatment of either a psychiatric or physical illness
* Subjects who are unable or unwilling to comply with restrictions and prohibited activities and treatments
* Subjects who are unable or unwilling to undergo venipuncture or tolerate venous access
* Subjects with prior surgery and/or chronic gastrointestinal dysfunction that may affect drug absorption, such as gastric bypass, gastrectomy, malabsorption, inflammatory bowel disease, chronic diarrhea
* Concurrent administration of medications or foods that are strong inhibitors of inducers of cytochrome p450 3A (CYP3A) within 2 weeks prior to study intervention. Duvelisib can increase exposure to CYP3A4 substrates; consider dose reduction of such substrates and monitor for signs of toxicities of co-administered sensitive CYP3A substrates.