A Phase 2 Study of CDX-011 (Glembatumumab Vedotin) for Metastatic Uveal Melanoma
Sapna P. Patel
Disease Group: Melanoma
Treatment Agent: CDX-011
Treatment Location: Both at MDACC & and Other Sites
Sponsor: National Cancer Institute
Primary Objectives The primary objective of this study is to characterize the clinical anti-tumor activity of CDX-011 (glembatumumab vedotin) as a single-agent in the treatment of patients with metastatic uveal melanoma. The primary endpoint will be overall response rate (ORR) using RECIST 1.1. Secondary Objectives Secondary objectives include a description of the clinical safety and benefit of CDX-011 (glembatumumab vedotin) and pharmacodynamics changes in glycoprotein NMB (GPNMB) expression. Secondary endpoints will include progression-free survival (PFS), overall survival (OS), GPNMB expression via immunohistochemistry (IHC). Exploratory Objectives Exploratory objectives for this study include characterization of the anti-tumor immunophenotype of patients receiving treatment. Post hoc, correlation of rash with clinical benefit, or lack of rash with lack of benefit, will also be explored.
IRB Review and Approval Date: 10/29/2015
Recruitment Status: Open
Projected Accrual: 35
1) Ability to understand and the willingness to sign a written informed
2) Patients must have histologically or cytologically confirmed metastatic or locally recurrent uveal melanoma. Because histologic or cytologic confirmation of primary uveal melanoma is not always possible the confirmation of the clinical diagnosis of uveal melanoma by the treating investigator is allowed. Clinical diagnosis of uveal melanoma is often made by an ophthalmologist, not by tissue diagnosis. If an ophthalmologist diagnosed and treated a patient for uveal melanoma in the past, it is sufficient for a clinical diagnosis.
3) Patients must have measurable disease, defined as at least one 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 >/=20 mm (>/=2 cm) with conventional techniques or as >=10 mm (>=1 cm) with spiral CT scan, MRI, or calipers by clinical exam. See Section 11 for the evaluation of measurable disease.
4) The study will be limited to patients who are chemotherapy-naïve. Patients may have received prior systemic or liver-directed local therapies for advanced uveal melanoma as long as those treatments do not involve chemotherapy. This includes, but is not limited to:, immunotherapy, targeted therapy, transarterial embolization, radiofrequency ablation, or cryoablation. Treatment must be completed at least 28 days prior to initiation of study therapy. Radiation therapy is also allowed and must be completed at least 28 days prior to initiation of study therapy. Lesions treated via radiation or liver-directed therapy may not be used as target lesions unless they demonstrate growth over a minimum of 3 months on subsequent imaging.
5) All prior treatment-related toxicities must be CTCAE v4 grade </=1 (except alopecia). Certain exceptions apply, such as immunotherapy-induced hypothyroidism or adrenal insufficiency or panhypopituarism requiring stable doses of hormone replacement or rash from prior therapy.
6) Age >/=18 years. Because no dosing or adverse event data are currently available on the use of CDX-011 (glembatumumab vedotin) in patients <18 years of age, children are excluded from this study but will be eligible for future pediatric trials.
7) ECOG performance status </=2
8) Life expectancy of greater than 3 months.
9) Patients must have normal organ and marrow function as defined: a.) leukocytes >/=3,000/µL b.)absolute neutrophil count >/=1,500/ µL c.)platelets >/=100,000/ µL d.) total bilirubin </=1.5 x institutional upper limit of normal e.) AST(SGOT)/ALT(SGPT) </=2.5 × institutional upper limit of normal; </=5 x institutional upper limit of normal if liver metastasis present f.) Creatinine </= institutional upper limit of normal OR g.)creatinine clearance >/=60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal
10) The effects of CDX-011 (glembatumumab vedotin) on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 4 months after last CDX-011 (glembatumumab vedotin) dose. Women of child-bearing potential must have a negative serum pregnancy test within 14 days prior to start of protocol treatment. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men and women treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of CDX-011 (glembatumumab vedotin) administration.
11) Inclusion of Women and Minorities: NIH policy requires that women and members of minority groups and their subpopulations be included in all NIH-supported biomedical and behavioral research projects involving NIH-defined clinical research unless a clear and compelling rationale and justification establishes to the satisfaction of the funding Institute & Center (IC) Director that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. Exclusion under other circumstances must be designated by the Director, NIH, upon the recommendation of an IC Director based on a compelling rationale and justification. Cost is not an acceptable reason for exclusion except when the study would duplicate data from other sources. Women of childbearing potential should not be routinely excluded from participation in clinical research.
1) Patients with a history of another malignancy except for those who
have been disease-free for 2 years. Patients with a history of
definitively treated non-melanoma skin cancer or squamous cell carcinoma
of the cervix are eligible. Patients with definitively treated in-situ
cancers are eligible, regardless of timeframe.
2) Patients with neuropathy > grade 1.
3) Patients who are receiving any other investigational agents. If the patient received a previous investigational or other agent or treatment, a washout period of 4 weeks is required.
4) Patients receiving any medications or substances that are substrates of CYP3A4will be closely monitored for toxicity. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated list; medical reference texts such as the Physicians’ Desk Reference may also provide this information. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product.
5) Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
6) HIV-positive patients on antiretroviral medications that are CYP3A4 substrates will be closely monitored. HIV-positive patients will be excluded if they have a CD4 count <200 as these patients have an increased risk of lethal infections when treated with marrow-suppressive therapy.
7) Pregnant or nursing women.
8) Patients who have previously received CDX-011 (glembatumumab vedotin) or other MMAE-containing agents.
9) Patients with a history of allergic reactions attributed to compounds of similar composition to dolastatin or auristatin (e.g. Auristatin PHE, Auristatin PE, and symplostatin).
Information and next steps
Sapna P. Patel
Melanoma Medical Oncology
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