Fast Track Designation for Novel Glioblastoma Treatment
The FDA has granted Fast Track designation for an investigational drug, rhenium nanoliposomes (RNL) for the treatment of patients with recurrent glioblastoma. The treatment is being evaluated in the NIH/NCI-supported, multi-center ReSPECT Phase I dose-finding clinical trial (NCT01906385). The trial's Data and Safety Monitoring Board approved proceeding to Cohort 6 of the trial, which includes increasing both the drug volume and radiation dose to 8.8 mL and 22.3 millicuries (mCi), respectively.
RNL is designed to safely, effectively, and conveniently deliver a very high dose of radiation, of up to 25 times greater concentration than currently used external beam radiation therapy, directly into the brain tumor for maximum effect.
Pediatric Disease Designation Granted for OXi-4503
The FDA granted designation to OXi4503 (combretastatin A1-diphosphate/CA1P) for treatment of acute myeloid leukemia (AML) due to genetic mutations that disproportionately affect pediatric patients as a drug for a "rare pediatric disease," as defined in section 529(a)(3) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 360ff(a)(3)).
OXi4503 in combination with standard chemotherapy drug cytarabine was generally well-tolerated by adult AML patients and a maximum tolerated dose (MTD) level of OXi4503 was identified as the recommended dose for further clinical development of this novel two-drug combination.
In 26 evaluable AML patients, there were four complete remissions (CR/CRi) and one partial remission (PR). The CR responses were associated with >1-year overall survival times. The combination therapy exhibited a manageable toxicity and a promising benefit to risk profile in older adults with relapsed AML. Four of the five objective responders were in the >=65-years poor prognosis age category with adverse cytogenetic features.
OXi4503 exhibited single-agent anti-leukemia activity in animal models of AML and in a Phase Ia clinical study for relapsed/refractory (R/R) AML. Notably, the combination of OXi4503 with cytarabine (ARA-C) in xenografted human AML models was more effective than either drug alone. The clinical safety profile of OXi4503 as a single agent has previously been evaluated in Phase Ia clinical trials.
In the NCT00977210 Phase I dose-finding study in 43 advanced solid tumor patients, OXi4503 doses were escalated from 0.06 to 15.4 mg/m2, and 8.5 mg/m2 was defined as the MTD. In the NCT01085656 Phase Ia trial designed to evaluate the safety profile, MTD, and recommended Phase II dose of OXi4503 in patients with R/R AML and myelodysplastic syndrome, a total of 18 patients were treated with single-agent OXi4503 and showed a manageable safety profile at single-agent dose levels up to of 7.81 mg/m2 and there was early evidence of possible single-agent anti-AML activity.
More recently, a Phase Ib study was performed to evaluate the safety, tolerability, and clinical activity of a combination of OXi4503 and the standard anti-AML drug ARA-C. The combination therapy exhibited a manageable toxicity and a promising benefit to risk profile in adults with relapsed AML. An MTD level of OXi4503 was identified as the recommended dose for further clinical development of this novel two-drug combination. In 26 evaluable AML patients, there were four complete remissions (CR/CRi) and one partial remission. The median overall survival time for the four patients who achieved a CR/CRi was 528 days (95% CI: 434-NA), which was significantly longer than the median overall survival time of 113 days (95% CI: 77-172) for the remaining 22 patients who did not achieve a CR (Log rank Chi-square = 11.8, P=0.0006).
Priority Review Application for Anti-BCMA CAR T-Cell Therapy Idecabtagene Vicleucel
The FDA has accepted for Priority Review a Biologics License Application (BLA) for idecabtagene vicleucel (ide-cel; bb2121), an investigational B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell immunotherapy, for the treatment of adult patients with multiple myeloma who have received at least three prior therapies, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody. The FDA has set a Prescription Drug User Fee Act goal date of March 27, 2021.
The BLA is based on results from the Phase II KarMMa study evaluating the efficacy and safety of ide-cel in 128 adults with heavily pre-treated and highly refractory multiple myeloma exposed to an immunomodulatory agent, proteasome inhibitor, and anti-CD38 antibody.
KarMMa (NCT03361748) is a pivotal, open-label, single-arm, multicenter, multinational, Phase II study evaluating the efficacy and safety of ide-cel in adults with relapsed and refractory multiple myeloma in North America and Europe. The primary endpoint of the study is overall response rate as assessed by an independent review committee according to the International Myeloma Working Group criteria. Complete response rate is a key secondary endpoint. Other secondary endpoints include time to response, duration of response, progression-free survival, overall survival, minimal residual disease evaluated by next-generation sequencing assay, and safety.
The study enrolled 140 patients, of whom 128 received ide-cel across the target dose levels of 150-450 x 106 CAR+ T cells after receiving lymphodepleting chemotherapy. All enrolled patients had received at least three prior treatment regimens, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody, and were refractory to their last regimen, defined as progression during or within 60 days of their last therapy.
Fast Track Designation of DKN-01 for Gastric & Gastroesophageal Junction Cancer
The FDA has granted Fast Track designation to DKN-01 for the treatment of patients with gastric and gastroesophageal junction adenocarcinoma whose tumors express high Dickkopf-1 protein (DKK1), following disease progression on or after prior fluoropyrimidine- and platinum-containing chemotherapy and, if appropriate, human epidermal receptor growth factor (HER2)/neu-targeted therapy.
DKN-01 is a humanized monoclonal antibody that binds to and blocks the activity of DKK1 protein, a modulator of Wnt/Beta-catenin signaling. DKK1 has an important role in tumor cell signaling and in mediating an immunosuppressive tumor microenvironment through enhancing the activity of myeloid-derived suppressor cells and downregulating NK ligands on tumor cells. DKN-01 has also received Orphan Drug Designation for the treatment of gastric and gastroesophageal junction cancer from the FDA.
DKN-01 is currently being evaluated in clinical trials for gastroesophageal, gynecologic, hepatobiliary, and prostate cancers. In September 2020, the first patient was dosed in the a combination study of DKN-01 plus tislelizumab, an anti-PD-1 antibody, in patients with gastric or gastroesophageal junction cancer.
IND Application for Compassionate Use Program for Ulixertinib
The FDA granted an Investigational New Drug (IND) application for an intermediate Expanded Access Program (EAP) for the ERK inhibitor ulixertinib (BVD-523). Ulixertinib is being developed as a treatment for patients with MAPK pathway aberrant cancer, including but not limited to KRAS, NRAS, HRAS, BRAF, MEK, and ERK mutations.
The EAP is open across the United States to adolescent and adult cancer patients who cannot access an open clinical trial for the investigation of ulixertinib (BVD-523). This intermediate-sized expanded access program (NCT04566393) is currently open and available for physicians interested in treating their patients.
Ulixertinib is a first-in-class and best-in-class small-molecule inhibitor of extracellular signal-regulated kinase (ERK) family kinases (ERK1 and ERK2) that is being developed as a novel anti-cancer drug. ERK kinases are downstream components of the mitogen-activated protein kinase (MAPK) signaling cascade (RAS-RAF-MEK-ERK). Ulixertinib has demonstrated promising early efficacy for patients with tumors harboring alterations in the MAPK pathway, including atypical (non-V600) BRAF alterations, for which there are currently no approved targeted agents.
This EAP provides ulixertinib for compassionate use in advanced cancer patients with a MAPK pathway-altered solid tumor(s) who have exhausted available therapies. The protocol aims to collect sufficient information about the patient's treatment to provide a complete and accurate case report to health authorities using real-world data collection to assess response to treatment, safety, tolerability, and quality of life.
Breakthrough Therapy Designation for Disitamab Vedotin in Urothelial Cancer
The FDA has granted Breakthrough Therapy designation for disitamab vedotin (RC48), a novel humanized anti-HER2 antibody drug conjugate (ADC), for the second-line treatment of patients with HER2-positive locally advanced or metastatic urothelial cancer who have also previously received platinum-containing chemotherapy treatment.
Earlier this year, the FDA granted clearance of an Investigational New Drug application for a Phase II clinical study in the United States and the grant of Fast Track designation for disitamab vedotin.
RC48 was developed to treat HER2-expressing solid tumors. It has a novel antibody with a higher affinity to HER2 compared to standard of care, and superior anti-tumor activity compared to other treatments in animal models. RC48 was the first ADC drug approved for human clinical trials in China and favorable safety profile has been observed in clinical trials. It is currently being studied in multiple late-stage clinical trials across solid tumor types.
Eganelisib in Combination for First-Line Treatment of Advanced TNBC
The FDA has granted Fast Track designation for eganelisib (IPI-549) in combination with a checkpoint inhibitor and chemotherapy for the treatment of patients with inoperable locally advanced or metastatic triple-negative breast cancer (TNBC) in the first-line setting. Patients are currently being enrolled in MARIO-3, an ongoing Phase II study to evaluate eganelisib in a novel triple combination frontline regimen with atezolizumab and paclitaxel protein-bound particles in TNBC.
Earlier this year, the FDA granted Fast Track designation for eganelisib in combination with the checkpoint inhibitor nivolumab for the treatment of advanced urothelial cancer which is being studied in MARIO-275, a controlled Phase II study in patients with advanced urothelial cancer.
MARIO-3 is a Phase I study to evaluate the addition of eganelisib to standard of care treatment with atezolizumab and paclitaxel protein-bound particles in a novel triple combination frontline regimen in patients with locally advanced and/or metastatic TNBC. The study is designed to enroll approximately 60 patients across two cohorts, approximately 30 patients with programmed death-ligand 1 (PD-L1) positive disease based on immunohistochemistry (IHC) and 30 patients with PD-L1 negative disease based on IHC.
The primary objective of the study is complete response rate as measured by RECIST v1.1 with assessments conducted through month 12. Secondary measures include objective response rate, time to complete remission, time to response, duration of complete response, duration of response, and progression-free survival.
Priority Review for Crizotinib in Pediatric ALK-Positive Anaplastic Large Cell Lymphoma
The FDA has accepted and granted priority review to a supplemental New Drug Application (sNDA) for crizotinib for the treatment of pediatric patients with relapsed or refractory systemic anaplastic large cell lymphoma (ALCL) that is anaplastic lymphoma kinase (ALK)-positive.
Crizotinib received Breakthrough Therapy designation for the ALK-positive ALCL indication in May 2018 and, if approved, would be the first biomarker-driven therapy for this type of pediatric lymphoma. The Prescription Drug User Fee Act goal date for a decision by the FDA is January 2020.
ALCL is a rare type of non-Hodgkin lymphoma, divided into ALK-positive or ALK-negative disease. Though the 5-year survival rate for children with cancer in the U.S. is now the highest it's ever been at 80 percent, children with cancer continue to face challenges in treating their disease, including rare tumor types, variations in medicine response, and prolonged risk of side effects.
The FDA submission is supported by the results from Study ADVL0912 (NCT00939770) and Study A8081013 (NCT01121588). Study ADVL0912 is a Phase I/II study conducted in collaboration with the Children's Oncology Group , evaluating the maximum dose that is safe and tolerable, and assessing clinical activity in pediatric patients with relapsed or refractory solid tumors and ALCL. Study A8081013 evaluated crizotinib in pediatric and adult patients with advanced malignancies known to be ALK-positive other than non-small cell lung cancer and included patients with relapsed or refractory ALCL. These two studies showed compelling antitumor activity in pediatric and adult patients who received crizotinib.