FDA Pipeline: Designations in Myeloma, Adenoid Cystic Carcinoma, and Kaposi Sarcoma, Plus ODAC Votes


This week, the U.S. Food and Drug Administration granted designations in relapsed or refractory multiple myeloma, adenoid cystic carcinoma, and Kaposi sarcoma; and the FDA’s Oncologic Drugs Advisory Committee (ODAC) held votes on treatments for tenosynovial giant cell tumor and acute myeloid leukemia.

Fast Track Designation for CLR 131 in Relapsed or Refractory Multiple Myeloma

The FDA granted Fast Track designation for CLR 131 for the fourth line or later treatment of relapsed or refractory multiple myeloma. CLR 131 is a small-molecule radiotherapeutic phospholipid drug conjugate designed to deliver cytotoxic radiation directly and selectively to cancer cells and cancer stem cells. It is currently being evaluated in the ongoing phase II CLOVER-1 clinical trial in patients with relapsed or refractory multiple myeloma and other select B-cell lymphomas.

CLOVER-1 is being conducted in approximately 10 leading cancer centers in the United States in patients with relapsed or refractory B-cell hematologic cancers. The hematologic cancers being studied in the trial include multiple myeloma, chronic lymphocytic leukemia/small lymphocytic lymphoma, lymphoplasmacytic lymphoma, marginal zone lymphoma, mantle cell lymphoma, and diffuse large B-cell lymphoma. The study's primary endpoint is clinical benefit response, with additional endpoints of overall response rate, progression-free survival, median overall survival, and other markers of efficacy following a fractionated dose of 15.625 mCi/m2 dose of CLR 131 administered on day 1 and day 8, with the option for a second dose cycle approximately 75–180 days later.

In addition to receiving the two fractionated doses of CLR 131, patients with multiple myeloma will receive 40 mg oral dexamethasone weekly for up to 12 weeks. Efficacy responses will be determined by the latest International Multiple Myeloma Working Group criteria. Efficacy for all lymphoma patients will be determined according to Lugano criteria.

Orphan Drug Designation for AL101 in Adenoid Cystic Carcinoma

The FDA’s Office of Orphan Products Development granted Orphan Drug designation to AL101, a potent and selective inhibitor of gamma secretase–mediated Notch signaling, for the treatment of adenoid cystic carcinoma.

Current treatment options for adenoid cystic carcinoma, an uncommon form of malignant neoplasm that arises within secretory glands, include surgery, chemotherapy and/or radiation therapy; however, there is no approved drug for the treatment of adenoid cystic carcinoma.

AL101 is a gamma secretase inhibitor developed as a Notch inhibitor for oncology indications. Notch signaling pathway plays an important role in tumorigenesis in several solid and hematological malignancies. Upon ligand binding of the Notch receptor, an important step in the activation of Notch receptors is cleavage by gamma secretase, which frees the Notch intracellular signaling domain.

AL101 is currently being studied in the phase II ACCURACY trial for patients with adenoid cystic carcinoma with Notch activating mutations.

Pomalidomide Granted Breakthrough Therapy Designation for HIV-Positive and -Negative Kaposi Sarcoma

The FDA granted Breakthrough Therapy designation to pomalidomide for the treatment of patients with human immunodeficiency virus (HIV)-positive Kaposi sarcoma who have previously received systemic chemotherapy, as well as patients with HIV-negative Kaposi’s sarcoma.

Kaposi sarcoma is a multicentric tumor caused by Kaposi sarcoma–associated herpesvirus, also called human herpesvirus-8. Patients suffer multiple lesions on the skin and oral mucosa and, at times, other organs such as the lungs or gastrointestinal mucosa. Kaposi sarcoma most commonly arises in persons infected with HIV. There is a substantial need for new treatments because there are no approved therapies for HIV-positive patients who are refractory to or intolerant of systemic chemotherapy. The disease is more highly prevalent in areas of the world where HIV treatments are less available, such as sub-Saharan Africa, and in some countries, is the most common tumor in men overall.

The Breakthrough Therapy designation was granted by the FDA on the basis of the results of a clinical study performed under a Cooperative Research and Development Agreement. The results of that study, published by Polizzotto et al in the Journal of Clinical Oncology, evaluated pomalidomide in patients with Kaposi sarcoma with or without HIV infection, many of whom had received prior cytotoxic chemotherapy.

FDA ODAC Votes in Favor of Pexidartinib for the Treatment of Selected Patients With TCGT

The FDA Oncologic Drugs Advisory Committee (ODAC) voted (12 yes, 3 no, none abstained) that the demonstrated benefit of pexidartinib outweighs the risks in the treatment of adult patients with symptomatic tenosynovial giant cell tumor (TCGT), which is associated with severe morbidity or functional limitations, and which is not amenable to improvement with surgery. Pexidartinib is an investigational, novel, oral small molecule that potently inhibits colony stimulating factor-1 receptor, which is a primary growth driver of abnormal cells in the synovium that cause TGCT.

The new drug application (NDA) for pexidartinib is currently under Priority Review in the United States, and the FDA is expected to decide whether to approve the application by August 3, 2019. The FDA will consider this week's vote as it reviews the NDA, although it is not obligated to follow the Committee’s recommendation.

The NDA submission is based on the results of the phase III ENLIVEN study of oral pexidartinib, the first placebo-controlled study of a systemic investigational therapy in patients with TGCT. The ENLIVEN study met its primary endpoint of tumor response rate by RECIST, which was 39% in pexidartinib-treated patients and 0% for placebo-treated patients at week 25 (P < .0001). 

In the ENLIVEN study, hepatic toxicities were more frequent with pexidartinib vs placebo. In the randomized phase I of the study, eight (13%) patients discontinued pexidartinib due to adverse events; one discontinuation was due to hypertension and seven were due to liver-related adverse events occurring within the first 2 months of treatment. Of the liver-related adverse events, three were serious nonfatal adverse events with increased bilirubin, one lasting about 7 months. In non-TGCT development studies using pexidartinib, two severe liver toxicity cases (one required liver transplant, one was associated with death) were observed.

FDA ODAC Votes No on Quizartinib for the Treatment of Relapsed or Refractory FLT3-ITD AML

Three FDA ODAC committee members voted yes and eight committee members voted no when asked if the results from the phase III QuANTUM-R trial demonstrated that treatment with quizartinib provides a benefit that outweighs the safety risks for patients with relapsed or refractory FLT3-ITD acute myeloid leumiea (AML).

The NDA for quizartinib is currently under Priority Review in the United States, and the FDA is expected to make a decision on approval by August 25, 2019. The NDA submission of quizartinib is based on the results of QuANTUM-R, which was the first randomized phase III study to show that a FLT3 inhibitor prolonged overall survival as an oral, single agent compared to chemotherapy in patients with relapsed or refractory FLT3-ITD AML.

In the study, the median treatment duration with quizartinib was 4 cycles of 28 days each vs 1 cycle in the salvage chemotherapy arm.

Incidence of treatment-emergent adverse events was comparable between patients who received single-agent quizartinib and those who received salvage chemotherapy. The most common adverse drug reactions (> 30%, any grade) in patients treated with quizartinib included infections, bleeding, nausea, asthenic conditions, pyrexia, febrile neutropenia, and vomiting, and the most common grade ≥ 3 adverse drug reactions (> 20%) were infection and febrile neutropenia. The most common laboratory adverse reactions (incidence > 50%) were decreased white blood cell count, decreased lymphocyte count, decreased hemoglobin, decreased neutrophil count, and decreased platelet count. QTcF > 500 msec occurred in 8 patients (3.3%), and 2 out of 241 patients discontinued quizartinib due to QTcF prolongation. There were no reported events of grade 4 QTcF prolongation (Torsades de Pointes, sudden death, or cardiac arrest) in the quizartinib arm. The safety profile observed in QuANTUM-R appears consistent with that observed at similar doses in the quizartinib clinical development program.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.