Less than two weeks after the start of a phase III trial with CPI-613 (devimistat) called Armada 2000 in relapsed or refractory acute myeloid leukemia (AML) by Rafael Pharmaceuticals Inc., the metabolic oncology space again moved forward significantly as the company launched a phase III experiment dubbed Avenger 500 to test the same compound in pancreatic cancer.

The study will evaluate CPI-613 in combination with the modified FOLFIRINOX (mFFX) regimen as first-line therapy in patients with metastatic adenocarcinoma of the pancreas. FOLFIRINOX will be used as the control arm against CPI-613 paired with mFFX. Patients ages 18 to 75 of both sexes with metastatic (stage IV) pancreatic disease, who have not previously been treated for their metastases and who bear an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 are eligible for enrollment, Newark, N.J.-based Rafael said, and interim analysis could be done as early as the second quarter.

CEO Sanjeev Luther told BioWorld that Paul Bingham "was the original discoverer of CPI-613 in cancer, and then it was developed by Cornerstone" Pharmaceuticals Inc., which changed its name to Rafael. Bingham serves as vice president of research for Rafael and shares the discovery credit for Rafael's Altered Metabolism Directed (AMD) platform with Zuzana Zachar, the company's director of research.

In phase I efforts, a single-center, open-label, dose-escalation study looked at the safety, tolerability and efficacy of CPI-613 in combination with mFFX as front-line therapy in patients with metastatic pancreatic tumors. Eighteen patients were treated at the maximum tolerated dose of 500 mg/m2. Overall, the regimen was well-tolerated. No deaths due to adverse events were reported and no patients died while on active treatment. Three patients had a complete radiographic response and 61 percent achieved an objective response, with a median overall survival (OS) of 19.9 months and median progression-free survival of 9.9 months.

Armada 2000, begun in late November, is designed to study CPI-613 in combination with high-dose cytarabine and mitoxantrone (CHAM) in older patients with AML. The study will compare the efficacy and safety of high-dose cytarabine and mitoxantrone (HAM, the control arm) with CHAM. Enrolling are patients 60 or older with relapsed or refractory AML and an ECOG performance status of 0-2. The primary efficacy endpoint will be complete remission (CR). Secondary endpoints include OS and complete response with partial hematologic recovery as well as safety.

Rafael said it has weighed AMD compounds against a wide array of established cancer cell lines in cell culture, including some of the more challenging tumor types and cell lines characterized as multidrug resistant. In all cases, the tested cell lines were 100 percent killed by the AMD compounds within the same drug concentration range. Cells derived from noncancerous tissues were tested and seemed unaffected by AMD compounds even at concentrations that are several-fold higher than those at which cancer cells from the same tissue of origin are killed.

The first metabolic oncology inhibitor won the U.S. go-ahead in the summer of 2017. That's when Idhifa (enasidenib), an oral AML therapy developed by Summit, N.J.-based Celgene Corp. and Agios Pharmaceuticals Inc., of Cambridge, Mass., won earlier-than-expected FDA approval following a priority review. Idhifa addresses AML patients with an isocitrate dehydrogenase-2 (IDH2) mutation, a group accounting for between 8 percent and 19 percent of AML patients, or about 1,200 to 1,500 people in the U.S. The FDA also cleared a companion diagnostic that can detect IDH2 gene mutations. Mutations in IDH2, a critical metabolic enzyme, result in elevated levels of the oncometabolite 2-hydroxyglutarate (2HG), which prevents differentiation of myeloblasts, leading to tumor formation and progression. By inhibiting IDH2, Idhifa (formerly AG-221) aims to reduce 2HG levels and restore myeloblast differentiation. (See BioWorld, April 8, 2014, and Aug. 2, 2017.)

AML remains hot as an indication. Late last month, Tokyo-based Astellas Pharma Inc. scored its first regulatory win in the U.S. blood cancer space with approval from the FDA for its oral AML drug, Xospata (gilteritinib). Previously cleared in Japan, the FMS-like tyrosine kinase 3 (FLT3) inhibitor was given the nod in the U.S. for relapsed or refractory AML patients who test positive for the mutation, which is often associated with increased risk of relapse and poor survival. The agency also approved an expanded indication for a companion diagnostic to identify patients most likely to benefit from the drug: the Leukostrat CDx FLT3 Mutation Assay, developed by Invivoscribe Technologies Inc., of San Diego. The test is already used to identify patients eligible for treatment with Basel, Switzerland-based Novartis AG's Rydapt (midostaurin), a therapy for adults with newly diagnosed FLT3-mutated AML that was approved in May 2017. (See BioWorld, May 1, 2017, and Nov. 29, 2018.)

Also last month, after more than a decade of development and a priority review, New York-based Pfizer Inc. won FDA approval for Daurismo (glasdegib), a new drug that, when used with low-dose cytarabine (LDAC), has been shown to increase overall survival vs. cytarabine alone by a median of about four months for certain patients intolerant of intensive chemotherapy. The regulator also approved a supplemental NDA in a similar indication for Venclexta (venetoclax), a drug marketed by North Chicago-based Abbvie Inc. and Roche Holding AG, of Basel, Switzerland. Daurismo, an oral smoothened receptor and hedgehog pathway inhibitor, was approved for use in combination with LDAC for the treatment of newly diagnosed AML in adults ages 75 or older or who have other co-morbidities that may preclude intensive chemo. (See BioWorld, Nov. 26, 2018.)

In pancreatic cancer, success is much harder to come by, though Rockville, Md.-based Rexahn Pharmaceuticals Inc. in October reported preliminary safety and efficacy data from the ongoing phase IIa trial with RX-3117 in combination with Abraxane (nab-paclitaxel, Celgene Corp.) in patients newly diagnosed with metastatic pancreatic cancer. Results rolled out at the National Cancer Institute Pancreatic Cancer Symposium in Bethesda, Md. Rexahn is conducting a two-stage study. The first was the dose-escalation phase with the optimal dose defined in May 2018; the combination was found safe and well-tolerated when given at the highest recommended dose for both agents. The second involves the expansion cohort, which is currently ongoing and targeting enrollment of 40 patients at the optimal dose. RX-3117's mechanism of action bodes well for safety. An oral small-molecule nucleoside in the works for not only pancreatic cancer, but also bladder cancer and other malignancies, the compound – once intracellularly activated (phosphorylated) by the enzyme uridine cytidine kinase, also known as 'UCK2' – is incorporated into the DNA and RNA of cancer cells and inhibits synthesis of both, which induces apoptotic cell death. UCK2 is overexpressed in a number of human tumors, but has a very limited presence in normal tissues. Full data are expected next year, though Rexahn may unveil more interim results at the ASCO Gastrointestinal Cancers Symposium in January in San Francisco. (See BioWorld, Dec. 7, 2018.)