Duvelisib in Combination with Nivolumab for Treatment of Unresectable Stage IIIB-IV Melanoma
18 Years and older, Male and Female
HCC 20-155 (primary)
NCI-2021-13070
Summary
This phase I/II trial studies the side effects and best dose of duvelisib in combination with nivolumab and to see how well they work in treating patients with stage IIIB-IV melanoma that cannot be removed by surgery (unresectable). Duvelisib is in a class of medications called kinase inhibitors. It works by blocking the signals that cause cancer cells to multiply. This helps to stop the spread of cancer cells. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving duvelisib and nivolumab may help re-sensitize melanoma tumors to respond to anti-PD1 therapy.
Objectives
PRIMARY OBJECTIVES:
I. To determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of duvelisib when combined with anti-PD1 therapy nivolumab by immunologic profiling and toxicity data. (Phase I)
II. To assess the anti-tumor activity of the combination of duvelisib and nivolumab therapy, comparing disease change documented in computed tomography (CT) measurements 12 weeks after initiation of therapy to baseline scans, and every 12 weeks thereafter. (Phase II)
SECONDARY OBJECTIVE:
I. To assess early (within 4 weeks) and late toxicities (after 4 weeks) of combination duvelisib and nivolumab. (Phase I)
II. To assess the anti-tumor activity of the combination of duvelisib and nivolumab therapy, comparing disease change documented in CT measurements 12 weeks after initiation of therapy to baseline scans, and every 12 weeks thereafter. (Phase I)
III. To assess the potential antitumor response of the combination of duvelisib and anti-PD1 therapy. (Phase II)
IV. To assess the duration of response with this combination. (Phase II)
V. To assess progression-free survival and overall survival. (Phase II)
VI. To assess the safety of the combination of duvelisib and anti-PD1 therapy. (Phase II)
VII. To evaluate differences in response between certain pre-specified subsets of melanoma patients, including those who progressed on anti-PD1 therapy within 3 months (early progressors) and those who progressed after 3 months (late progressors), as well as by BRAF mutation status. (Phase II)
EXPLORATORY OBJECTIVES:
I. To evaluate how immune cell populations change by duvelisib dose, to help inform recommended phase II dosing.
II. To evaluate the effects of duvelisib on the tumor microenvironment (TME).
III. To explore mechanism of anti-PD1 resistance and the role of duvelisib in overcoming this resistance.
OUTLINE: This is a phase I, dose-escalation study of duvelisib followed by a phase II study.
Patients receive duvelisib orally (PO) once daily (QD) or twice daily (BID) on days 1-28. Patients also receive nivolumab intravenously (IV) over 30 minutes on days 1 and 14 of cycles 1-4 and day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 28 days and then every 3 months for up to 5 years.
Eligibility
- American Joint Committee on Cancer (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
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 or Karnofsky >= 60%
- Hemoglobin >= 9.0 g/dL
- Absolute neutrophil count >= 1500 cells/uL
- Platelets >= 100,000 cells/uL
- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN). Patients with Gilbert's syndrome must have normal direct bilirubin
- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x 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 >= 10 mm with CT scan, magnetic resonance imaging (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-principal investigator (PI)s
- Duvelisib and nivolumab therapy may be harmful for a developing fetus. Women of child bearing potential (WCBP) must have a negative urine or serum beta human chorionic gonadotropin (beta hCG) 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
**Clinical trials are research studies that involve people. These studies test new ways to prevent, detect, diagnose, or treat diseases. People who take part in cancer clinical trials have an opportunity to contribute to scientists’ knowledge about cancer and to help in the development of improved cancer treatments. They also receive state-of-the-art care from cancer experts...
Click here to learn more about clinical trials.