Duvelisib in Combination With Nivolumab in Patients With Advanced Unresectable Melanoma

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase I/II Study of PI3Kγδ Inhibitor Duvelisib in Combination With Nivolumab in Patients With Advanced Unresectable Melanoma Who Have Progressed on Anti-PD1 Therapy

Conditions
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Unresectable Melanoma

Intervention / Treatment
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* Drug: Nivolumab
* Drug: Duvelisib


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Duvelisib plus Nivolumab<br>Phase 1: Duvelisib will be taken orally in doses from 15mg once a day, 25mg once a day or 25mg twice a day, 12 hours a part, to determine the recommended dose for the Phase II study when combined with nivolumab. Nivolumab, 240mg, IV, every 2 weeks for the first four cycles; thereafter it may be switched to 480mg, IV, once every 4 weeks if deemed appropriate by the study doctor. Phase II: The Recommended Phase II dosage of duvelisib administered will not be determined until Phase I is completed. Nivolumab, 480mg, IV, every 4 weeks, for up to 1 year. | Drug: Nivolumab<br>* Nivolumab is a human IgG4 monoclonal antibody that blocks PD-1. It is a type of immunotherapy and works as a checkpoint inhibitor, blocking a signal that prevents activation of T cells from attacking the cancer.<br>* Other names: AG013736;Drug: Duvelisib<br>* Duvelisib is a potent inhibitor of both γ and δ isoforms. Duvelisib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.<br>* Other names: Copiktra;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MTD / Recommended Phase II dose (RP2D) of duvelisib with nivolumab | The Maximun Tolerated Dose / RP2D will be determined via specified acute dose limiting toxicities (DLTs) and laboratory abnormalities considered possibly related to study treatment, occurring from the initial dose of duvelisib + nivolumab through day 28 of treatment (acute), which will be considered for decisions to continue enrollment at the current dose level or proceed to the next dose level. Toxicities occurring from day 29 through 28 days after completion of treatment will be considered late toxicities. Acute and late toxicities will be considered when deciding on the RP2D. The highest dose level (Maximum Tolerated Dose) at which ≤ 1 of 6 treated patients experiences a DLT will determine the RP2D. DLTs are defined using National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. | Up to 56 days (per patient) | 
| Overall Response Rate (ORR) | Complete response [CR] + partial response [PR], per RECIST v1.1 criteria. Per RECIST v1.1, CR: Disappearance of all target lesions. Any pathological lymph nodes(whether target or non-target) must have reduction in short axis to <10 mm. For non-target lesions: Disappearance of all non-target lesions and normalization of tumormarker level. All lymph nodes must be non-pathological in size (<10mm short axis);PR: At least a 30% decrease in the sum of diameters of target lesions, taking asreference the baseline sum diameters. | Up to 36 months | 
| Change in CD +8 TIL frequency | CyTek flow cytometry will be used to evaluate tumor-infiltrating cells in PBMCs and tumor tissue for the increased frequency (proliferation) and activation of CD8+ TILs. Proliferation of CD8+ TIL cells correlate with improved survival in patients with melanoma. | At baseline and 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Adverse Events at least possibly related to treatment | Acute (within 28 days after start of treatment) and late toxicities (29 to 56 days post start of treatment) rates occurring within 56 days of start of treatment, as graded by CTCAE v5.0 in patients at each dosing interval and in the expansion cohort. Toxicity events include those that are possibly, probably or definitely related to study treatment per Criteria for Adverse Events version 5 (CTCAE v5.0). | Up to 56 days | 
| Clinical Benefit | Complete response [CR] + partial response [PR] + stable disease [SD], per RECIST v1.1 criteria . Per RECIST v1.1, CR: Disappearance of all target lesions. Any pathological lymph nodes(whether target or non-target) must have reduction in short axis to <10 mm. For non-target lesions: Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10mm short axis);PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; 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. | Up to 36 months | 
| Duration of Response | The (median) length of time from which measurement criteria are first met for Complete Response (CR) or Partial Response (PR) until the first time at which progressive disease is objectively documented per RECIST v1.1. CR: Disappearance of all target lesions. Any pathological lymph nodes(whether target or non-target) must have reduction in short axis to <10 mm. For non-target lesions: Disappearance of all non-target lesions and normalization of tumormarker level. All lymph nodes must be non-pathological in size (<10mm short axis);PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. | Up to 36 months | 
| Progression-free Survival (PFS) | The (median) length of time from the initial date of treatment to the date of documented progression, or the date of death due to any cause (in the absence of progression, whichever occurs first), with progression defined by RECIST v1.1. PerRECIST v1.1, progressive disease is defined as at least a 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). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm. For non-target lesions, PD: Unequivocal progression of existing non-target lesions. The appearance of one or more new lesions is also considered progression. | Up to 36 months | 
| Overall Survival (OS) | The (median) length of time from the start of treatment that patients remain alive, until death from any cause. | Up to 5 years | 
| Adverse events graded by CTCAE v5.0 | Percentage of toxicity events that are possibly, probably or definitely related to study treatment per Criteria for Adverse Events version 5 (CTCAE v5.0). | Up to 39 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Anti-PD-1 monoclonal antibody (mAb)