FDA Pipeline: Applications and Designations in Prostate Cancer, Leukemia, and HER2-Positive Cancers


In the past 2 weeks, the U.S. Food and Drug Administration (FDA) accepted a new drug application and granted Priority Review for a prostate cancer treatment, granted Orphan Drug designation to a treatment for acute lymphoblastic leukemia, accepted an investigational new drug application for a product targeting HER2-positive solid tumors, lifted a partial clinical hold on a phase I trial in acute myeloid leukemia, and announced a forthcoming public meeting on higher-dose opioid analgesics.

New Drug Application and Priority Review for Darolutamide in Nonmetastatic Castration-Resistant Prostate Cancer

The FDA accepted a new drug application (NDA) and granted Priority Review to darolutamide for the treatment of nonmetastatic castration-resistant prostate cancer. Darolutamide is an investigational, nonsteroidal androgen receptor antagonist with a distinct chemical structure that binds to the receptor, inhibiting the growth of prostate cancer cells.

The NDA and Priority Review status were based on data from the phase III ARAMIS trial in men with nonmetastatic castration-resistant prostate cancer. ARAMIS is a randomized, multicenter, double-blind, placebo-controlled trial evaluating the safety and efficacy of oral darolutamide in patients with nonmetastatic castration-resistant prostate cancer who are currently being treated with androgen-deprivation therapy as standard of care and are at high risk for developing metastatic disease. Approximately 1,500 patients were randomly assigned in a 2:1 ratio to receive 600 mg of darolutamide twice a day or placebo along with androgen-deprivation therapy.

The primary endpoint of this trial is metastasis-free survival defined as time between randomization and evidence of metastasis or death. The secondary endpoints are overall survival, time to pain progression, time to initiation of first cytotoxic chemotherapy, time to first symptomatic skeletal event, and characterization of the safety and tolerability of darolutamide.

Orphan Drug Designation for AUTO3 in Acute Lymphoblastic Leukemia

The FDA granted Orphan Drug designation to autologous enriched T cells genetically modified with a retroviral vector to express two chimeric antigen receptors targeting CD19 and CD22 (AUTO3) for the treatment of acute lymphoblastic leukemia (ALL).

Despite a high rate of response to induction chemotherapy, only 30% to 40% of adult patients with ALL will achieve long-term remission. Similarly, pediatric patients typically respond well to first-line treatment (combination chemotherapy), but 10% to 20% of patients relapse with chemotherapy-resistant disease, leading to a significant unmet need in pediatric patients with high-risk relapsed or refractory ALL.

AUTO3 is a programmed T-cell therapy containing two independent chimeric antigen receptors targeting CD19 and CD22 that have each been independently optimized for single-target activity. By simultaneously targeting two B-cell antigens, AUTO3 is designed to minimize relapse due to single antigen loss in patients with B-cell malignancies. AUTO3 is currently being tested in pediatric ALL in the AMELIA trial and in diffuse large B-cell lymphoma in the ALEXANDER trial.

Investigational New Drug Application Accepted for MT-5111 in Patients With HER2-Positive Cancers

The FDA accepted an investigational new drug (IND) application for MT-5111, an engineered toxin body targeting HER2.

MT-5111 consists of a single-chain variable fragment with affinity for HER2, fused to the enzymatically active deimmunized Shiga-like toxin-A subunit (SLTA). MT-5111 specifically binds and kills HER2-expressing cells in a manner consistent with SLTA-mediated cellular cytotoxicity. MT-5111 has been specifically designed to avoid competition with and to overcome the primary mechanisms of tumor resistance to current HER2-targeted therapies. MT-5111 represents a novel HER2-targeted therapy that could provide benefit in subjects with HER2-positive cancers and potentially overcome mechanisms of tumor resistance to existing HER2-targeted therapies.

A phase I study in relapsed or refractory patients with HER2-positive solid tumors is planned for 2019. The trial is an open-label, dose-escalation and dose-expansion study of MT-5111 given as monotherapy in subjects with HER2-positive solid tumors. The primary objective of the trial is to evaluate the safety and tolerability of MT-5111 and to determine the recommended phase II dose in subjects with advanced HER2-positive solid tumors.

Partial Clinical Hold Lifted on Phase I Study of XmAb14045

The FDA lifted the partial clinical hold that was placed on the phase I study of XmAb14045, a CD123 × CD3 bispecific antibody molecule being evaluated in patients with relapsed or refractory acute myeloid leukemia and other CD123-expressing hematologic malignancies. The decision follows discussion and agreement with the FDA on amendments to the study protocol, including guidance on the monitoring and clinical management of cytokine-release syndrome.

“We are working with investigational sites to resume enrollment based on the amended protocol, through which we have sought to enhance the safety of patients participating in the study,” said Paul Foster, MD, Senior Vice President and Chief Medical Officer at Xencor.

FDA Announces Public Meeting to Discuss Safety and Utility of Higher-Dose Opioid Analgesics

The FDA announced this week that the agency will be holding a public advisory committee meeting on June 11 and 12 to discuss safety concerns that have been raised concerning the safe prescribing and use of the higher-range doses of opioids. This is a joint meeting of the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee.

The agency is interested in learning more about how health-care professionals are using these drugs in clinical practice and situations that may warrant the use of higher doses of opioid analgesics. The meeting will also address the magnitude and frequency of harms associated with higher doses of opioid analgesics relative to lower doses, as well as optimal strategies for managing these risks while ensuring access to appropriate pain management for patients.

The FDA meeting will include discussions about:

  • The specific clinical use of higher product strengths and daily doses; medical situations that may warrant pain management with these medications; and factors influencing prescribing practices
  • Identifying specific patient populations for whom there may be clear benefits in prescribing these medications at higher doses
  • The magnitude and frequency of harms associated with opioid analgesics at higher product strengths and daily doses, relative to lower strengths and daily doses, including the role of opioid dose in adverse health outcomes in both patients and others who may access the drugs, such as those at risk of developing addiction or experiencing a fatal overdose
  • Potential FDA actions that may address these issues, as well as the expected impact any such actions may have on patients and public health more broadly.

The FDA intends to make background material available to the public no later than 2 business days before the meeting.

“As part of our work to explore innovative approaches to reduce exposure to opioids, we’re seeking public input on the safe prescribing of higher-strength opioids and the serious safety concerns associated with higher strengths and higher daily doses of opioid analgesics.…,” said Douglas Throckmorton, MD, Deputy Center Director for Regulatory Programs in the FDA’s Center for Drug Evaluation and Research. “Through this public dialogue, our goal is to better understand what necessary steps we may need to take to ensure that only patients who truly need these medications gain access to them.”

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®.