FDA Grants Fast Track Designation for CLR 131 in LPL/WM

May 26, 2020

The FDA granted fast track designation for CLR 131 in lymphoplasmacytic lymphoma/Waldenstrom’s macroglobulinemia in patients having received 2 prior treatment regimens or more.

The FDA has granted fast track designation for CLR 131 in lymphoplasmacytic lymphoma (LPL)/Waldenstrom’s macroglobulinemia (WM) in patients having received 2 prior treatment regimens or more, according to Cellectar Biosciences, the developer of the agent.1

CLR 131 is a small-molecule, cancer-targeting radiotherapeutic Phospholipid Drug Conjugate (PDC) designed to deliver cytotoxic radiation directly and selectively to cancer cells and cancer stem cells. Currently, CLR 131 is being evaluated in the company’s ongoing phase II CLOVER-1 clinical study in patients with relapsed or refractory multiple myeloma and LPL/WM.

“LPL/WM patients that do not respond optimally or are intolerant of ibrutinib, currently have limited treatment options and poor survival rates,” James Caruso, president and CEO of Cellectar, said in a press release. “Fast Track Designation for LPL/WM further supports our clinical development strategy to quickly and efficiently provide these patients with an effective therapeutic alternative.” 

Earlier this year, the company announced that it had received orphan drug designation for CLR 131 in LPL.

In February 2020, Cellectar announced positive data from the phase II CLOVER-1 study.2 Additionally, the company announced the successful completion of its phase I dose escalation study. 

Data from the studies demonstrated activity in all indications tested, including multiple myeloma, diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), and LPL/WM. 

Patients in the studies were heavily pre-treated, with patients with multiple myeloma having a median of 5 prior treatment regimens (range, 3-17), which included immunomodulatory drugs, proteasome inhibitors, and CD38 antibodies for the majority of patients. Additionally, a majority of the patients (51%) were quad refractory or greater and 44% of all treated multiple myeloma patients were triple class refractory. Patients with NHL in the study were also heavily pre-treated, having had a median of 3 prior lines of treatment (range, 1-9) with the majority of patients being refractory to rituximab and/or ibrutinib.

Patients with relapsed or refractory multiple myeloma were treated with 3 different doses (<50mCi, ~50mCi and ~75mCi total body dose [TBD]; the <50mCi total body dose was a deliberately planned sub-therapeutic dose). Patients who received the highest dose of CLR 131 demonstrated a 42.8% overall response rate (ORR), and those who received ~50mCi TBD had a 26.3% ORR with 100% of all evaluable patients (n=43) achieving the primary outcome measure of clinical benefit as defined by having stable disease or better. Moreover, 85.7% of patients with multiple myeloma receiving the higher total body dose levels of CLR 131 experienced tumor reduction. Even further, the 75mCi TBD demonstrated positive activity in both high-risk patients and triple class refractory patients with a 50% and 33% ORR, respectively.

“For patients who have failed the current standard of care treatments for any of these indications, there is a need for additional treatment options,” lead study investigator Sikander Ailawadhi, MD, from the Mayo Clinic, said in a press release. “These data are impressive, especially in these very difficult to treat patient populations. CLR 131 offers a very attractive safety and efficacy profile.”

The most frequently reported adverse events (AEs) in patients with relapsed or refractory multiple myeloma were cytopenias, which followed a predictable course and timeline. The most common grade ≥3 AEs at the highest dose were hematologic toxicities including thrombocytopenia (65%), neutropenia (41%), leukopenia (30%), anemia (24%) and lymphopenia (35%). Notably, no patients experienced cardiotoxicities, neurological toxicities, infusion site reactions, peripheral neuropathy, allergic reactions, cytokine release syndrome, keratopathy, renal toxicities, or changes in liver enzymes. The safety and tolerability profile in patients with relapsed/refractory NHL was the same except for fewer cytopenias of any grade.

In addition to these findings, subtype assessments were completed in patients with relapsed or refractory B-cell NHL. Patients with DLBCL demonstrated a 30% response rate, with 1 patient achieving a complete response, which continued at nearly 24 months post-treatment. The response rate for CLL/SLL/MZL patients was 33%. Only 2 patients with MCL were enrolled, with stable disease as the best response.

Additionally, data from the company’s phase II CLOVER-1 clinical study showed that 4 LPL/WM patients demonstrated 100% ORR, with 1 patient achieving a complete response which continued at nearly 27 months.

“All four LPL/WM patients treated in our CLOVER-1 phase II study to date achieved a 100% overall response rate and a 25% complete response rate,” said Caruso. “This strong response rate may represent an important improvement in the treatment of relapsed/refractory LPL/WM as no approved or late-stage development treatments for relapsed or refractory patients have reported complete responses.”

References:

1. Cellectar Receives FDA Fast Track Designation for CLR 131 in Lymphoplasmacytic Lymphoma/Waldenstrom’s Macroglobulinemia [news release]. Florham Park, NJ. Published May 26, 2020. globenewswire.com/news-release/2020/05/26/2038539/0/en/Cellectar-Receives-FDA-Fast-Track-Designation-for-CLR-131-in-Lymphoplasmacytic-Lymphoma-Waldenstrom-s-Macroglobulinemia.html. Accessed May 26, 2020. 

2. Cellectar Biosciences Announces CLR 131 Achieves Primary Efficacy Endpoints from Its Phase 2 CLOVER-1 Study in Relapsed/Refractory B-cell Lymphomas and Completion of the Phase 1 Relapsed/Refractory Multiple Myeloma Dose Escalation Study [news release]. Florham Park, NJ. Published February 19, 2020. globenewswire.com/news-release/2020/02/19/1986939/0/en/Cellectar-Biosciences-Announces-CLR-131-Achieves-Primary-Efficacy-Endpoints-from-Its-Phase-2-CLOVER-1-Study-in-Relapsed-Refractory-B-cell-Lymphomas-and-Completion-of-the-Phase-1-Re.html. Accessed May 26, 2020.