NORWALK, Conn. & MADISON, Wis.—The Multiple Myeloma Research Consortium (MMRC) announced Sept. 22 that it has opened six new clinical trials in 2014, says they “represent some of the most promising and brand new treatments in development today,” and is on track to open more multiple myeloma clinical trials during 2014 than any other year since the consortium was founded in 2004. And, a little under three weeks earlier, Cellectar Biosciences Inc. announced that the U.S. Food & Drug Administration (FDA) has accepted the company’s investigational new drug (IND) application to begin clinical study of I-131-CLR1404, a highly selective cancer-targeting radiopharmaceutical, in patients with relapsed or refractory multiple myeloma.
“Together, with our committed and world-class partners, we have opened six incredibly exciting new trials for multiple myeloma patients who are running out of treatment options,” said Dr. Fiona An, senior vice president of clinical research for the Multiple Myeloma Research Foundation (MMRF) and MMRC. “We have such a robust pipeline of promising investigational agents—from monoclonal antibodies to first in class novel therapy to all oral regimens—and we are confident that they can prove to have a significant impact for many of our patients.”
The MMRC-related trials are:
- A Phase 1, multicenter, open-label, dose-escalation combination study of marizomib, pomalidomide, and low-dose dexamethasone in subjects with relapsed or refractory multiple myeloma. Marizomib is a novel proteasome inhibitor from Triphase, in the same class as Velcade (bortezomib) and Kyprolis (carfilzomib), that has been studied in a Phase 1 single-agent trial in the MMRC. Investigators believe that it can work in patients who are resistant to other proteasome inhibitors.
- A multicenter, Phase 1/2b study of ibrutinib, in combination with Kyprolis in subjects with relapsed or relapsed and refractory multiple myeloma. Ibrutinib blocks a protein called Bruton’s tyrosine kinase and is an oral drug already approved by FDA for patients with mantle cell lymphoma and chronic lymphocytic leukemia who have received at least one prior therapy, and for all patients with Deletion 17 p CLL.
- A Phase I study of the combination of a selective inhibitor of nuclear export called Selinexor (KPT-330), with Kyprolis and dexamethasone in patients with relapsed or relapsed/refractory multiple myeloma. Selinexor is the first in a new class of drugs to be tested in multiple myeloma, and the MMRF played a key role in prioritizing multiple myeloma as an early indication by providing Karyopharm, the manufacturer, with a Biotech Investment Award in 2010.
- A Phase I study of SAR650984 in combination with Kyprolis for the treatment of relapsed or refractory multiple myeloma. SAR650984 is an anti-CD 38 monoclonal antibody therapy that was previously studied in combination with Revlimid and dexamethasone in the MMRC. Early results show that this treatment can be effective—even as a single agent—in patients who have failed all other options.
- A Phase I/II trial of ixazomib (MLN9708) in combination with Pomalyst (pomalidomide) and dexamethasone for relapsed or relapsed refractory multiple myeloma. Previous Phase I and II research with ixazomib in combination with lenalidomide and dexamethasone in newly diagnosed patients found high response rates and increased depth of response. Ixazomib is a once-a-week pill that has the potential to enable the first all-oral proteasome-based treatment regimen.
- A Phase I, open label, dose-escalation first-in-man study of CB-5083, the first p97 inhibitor to enter clinical trials. Several MMRC member institutions worked closely with manufacturer Cleave Biosciences on the preclinical work, which suggested activity in multiple myeloma. CB-5083 targets a novel protein, p97 that is involved in various aspects of protein homeostasis and the proteasome pathway and inhibits this pathway at a novel intervention point compared to the proteasome inhibitors, Velcade and Kyprolis. This is a mechanistically distinct way of inhibiting this critical pathway and may provide benefit for patients who are relapsed and refractory.
“The ability of our myeloma focused clinicians to rapidly move laboratory data into real world clinical trials is a real strength of the consortium,” said Dr. Sagar Lonial, vice chairman of clinical affairs in the Department of Hematology and Medical Oncology of the Winship Cancer Institute at Emory University and chairman of the MMRC Steering Committee and Project Review Committee. “New treatments and combinations represent the future of how we will treat myeloma. The strides made just this year will help our patients in their goals to control and ultimately cure the disease.”
Meanwhile, Cellectar Biosciences’ IND-stage compound, I-131-CLR1404, is radiotherapeutic comprised of a proprietary phospholipid ether (PLE) analog, acting as a cancer-targeted delivery and retention vehicle, covalently labeled with Iodine-131, a cytotoxic radioisotope that is already commonly used to treat thyroid and other cancer types.
Cellectar’s says that because its PLE platform has been shown to “reliably and universally accumulate in malignant cancer cells, and the therapeutic properties of the Iodine-131 isotope are well known,” I-131-CLR1404 is engineered to combine an intracellular radiation mechanism of destroying cancer cells, including cancer stem cells, through targeted delivery specific to malignant tissue that spares critical normal tissues from consequential radiation dose.
Cellectar plans to initiate a Phase 1/2, proof-of-concept trial during the fourth quarter 2014 in approximately 20 patients with relapsed or refractory multiple myeloma that have previously been treated with, or are intolerant of, an immunomodulator and a proteasome inhibitor. The primary objective of the study will be to determine the safety and tolerability of I-131-CLR1404, with and without concurrent weekly dexamethasone. In addition, the trial will seek to identify the recommended dose for future pivotal trials and determine therapeutic activity of I-131-CLR1404 in this patient population as measured by overall response rate, time to progression and duration of response.
“This trial affords us an opportunity to both assess the safety of I-131-CLR1404 in patients with multiple myeloma, but also to obtain near-term proof-of-concept data characterizing the activity of I-131-CLR1404 in this difficult-to-treat patient population,” said Dr. Simon Pedder, president and CEO of Crllectar. “Having initiated a Phase 2 diagnostic imaging trial of our lead compound, I-124-CLR1404, in glioblastoma earlier in the year, we are pleased to now have this opportunity to initiate a second, company-sponsored clinical trial with the potential to showcase the therapeutic applications of our targeted delivery platform.”