Duvelisib in Combination With Nivolumab in Patients With Advanced Unresectable Melanoma

NCT04688658 | Terminated Phase 1 Results DMC FDA Drug

• 1 other identifier: HCC 20-155
• Study Type: interventional
• Target: 13
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Unresectable Melanoma

Keywords

Anti-PD-1 monoclonal antibody (mAb)

Outcome Measures

Primary Outcomes (6)

• DLTs by Phase I Dose of Duvelisib With Nivolumab

  Number of patients experiencing 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) or toxicities occurring from day 29 through 28 days after completion of treatment (late toxicities). DLTs are defined using National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

  Up to 56 days (per patient)

• Best Overall Response

  Best Response per RECIST v1.1: Completed Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (\<10mm short axis); Partial Response (PR): At least a 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 Progressive Disease (PD), taking as reference the smallest sum diameters while on study. Progressive Disease (PD): ≥20% (relative) increase in sum of diameters of target lesions referencing smallest sum on study (includes baseline sum if is smallest on study) and, the sum must also demonstrate an absolute increase of at least 5 mm; appearance of one or more new lesions.

  Up to 29 months

• Best Overall Response Rate (ORR)

  Proportion of patients with a Best Response (CR+PR)/(CR+PR+SD+PD) per RECIST v1.1 of Completed Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (\<10mm short axis); or Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

  Up to 29 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.

  Baseline to Week 4

• 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.

  Baseline to Week 12

• 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.

  Week 4 to Week 12

Secondary Outcomes (26)

• Clinical Benefit

  At Week 12

• Clinical Benefit

  At Week 24

• Clinical Benefit

  At Week 48

• Clinical Benefit Rate

  At Week 12

• Acute Adverse Events at Least Possibly Related to Treatment

  Up to 4 weeks

Other Outcomes (4)

• Immune Cell Function

  Baseline (prior to treatment), at 12 weeks after start of treatment; Up to 2 years (cohort)

• Immune Cell Function

  Baseline (prior to treatment), at 12 weeks after start of treatment; Up to 2 years (cohort)

• Tumor Microenvironment (TME)

  Baseline (prior to treatment), at 12 weeks after start of treatment; Up to 2 years (cohort)

Study Arms (1)

Duvelisib plus Nivolumab

EXPERIMENTAL

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; Drug: Duvelisib

Interventions

Nivolumab DRUG

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.

Also known as: Opdivo, AG013736

Duvelisib plus Nivolumab

Duvelisib DRUG

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.

Also known as: Copiktra

Duvelisib plus Nivolumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• John Kirkwood: lead
• Secura Bio, Inc.: collaborator
• Bristol-Myers Squibb: collaborator

Study Sites (1)

UPMC Hillman Cancer Center

Pittsburgh, Pennsylvania, 15232, United States

Location

MeSH Terms

Interventions

Nivolumab; Axitinib; duvelisib

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Benzamides; Amides; Organic Chemicals; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Indazoles; Pyrazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Results Point of Contact

• Title: Barbara Stadterman, MPH, CCRP
• Organization: UPMC Hillman Cancer Center

stadtermanbm@upmc.edu

4126475554

Study Officials

• John Kirkwood, MD

  UPMC Hillman Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor of Medicine

Study Record Dates

• First Submitted: December 23, 2020
• First Posted: December 30, 2020
• Study Start: October 6, 2021
• Primary Completion: February 22, 2024
• Study Completion: February 1, 2025
• Last Updated: December 17, 2025
• Results First Posted: December 17, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)