Investigators Aim at B-Cell Malignancies Using Targeted Radiopharmaceutical

OncologyLive, Vol. 20/No. 20, Volume 20, Issue 20

In the phase II CLOVER-1 trial, investigators are evaluating whether CLR 131 will be an effective option for patients with difficult-to-treat relapsed or refractory B-cell lymphomas.

Laura Finn, MD

In the phase II CLOVER-1 trial (NCT02952508), investigators are evaluating whether CLR 131, a first-in-class radioiodinated phospholipid drug conjugate that selectively delivers radiation to malignant cells, will be an effective option for patients with difficult-to-treat relapsed or refractory (R/R) B-cell lymphomas. Results have so far been presented from the multiple myeloma (MM) and diffuse large B-cell lymphoma (DLBCL) cohorts.

“It’s important to start developing new mechanisms of action for the ongoing treatment of these blood cancers,” CLOVER-1’s principal investigator, Laura Finn, MD, said. This is especially applicable to MM, a disease setting in which radiation therapy (RT) has been mostly palliative rather than curative.1

“We really only offer radiation therapy to patients who have bone lesions or plasmacytomas. I find that this is a unique option for those with MM, because like all blood cancers, there are very few instances when we would apply RT. CLR 131 falls into a niche category for patients with MM, where they can receive systemic radiation for a blood cancer. This is a whole new therapeutic option for [these] patients,” said Finn, director of Hematology and the Bone Marrow Transplant Program at Ochsner Health System in Louisiana.

CLOVER-1 is enrolling roughly 80 patients who previously received standard of care (SOC) therapy for MM, indolent chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), lymphoplasmacytic lymphoma (LPL), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), or DLBCL. B-cell lymphomas are the most common hematologic malignancy and are associated with poor response. Complete or partial response in these disease types can be as low as 2% to 4%, translating to a need for expanded treatment options.2

CLOVER-1’s primary endpoint is clinical benefit rate. Its secondary endpoints are preliminary efficacy, defined as overall response rate (ORR), time to progression, and overall survival.

Composed of proprietary phospholipid ethers (CLR 1404) that share a covalent link with the cytotoxic radioisotope iodine 131 (131I), CLR 131 is an intravenous radiopharmaceutical that is designed to deliver cytotoxic radiation directly to tumor cells, minimizing tissue damage to normal cells.

“CLR 131 exploits malignant cells’ selective uptake and retention of phospholipid ethers. This membrane compound is unique to the malignant cells and is how the therapy can be targeted to the cancer cells with very little off-target effect from the drug,” Finn said. Phospholipids, which form the bilayer structures of cell membranes, are an essential component of all cells and have been shown to increase with oncogenesis and tumor progression.

CLR 131 spares normal tissue because it is taken up by lipid raft microdomains expressed on tumor cells and accumulates in the cytoplasm of tumor cells. This delivers cytotoxic 131I directly to the cancer cells and induces apoptosis.

CLR 131 received an FDA fast track designation in fourth line or later R/R MM in May.3 In July, it was fast tracked in R/R DLBCL.4

In February 2019, CLR 131’s developer, Cellectar Biosciences, of Florham Park, New Jersey, reported positive top-line results from the R/R MM cohort of CLOVER-1. In the first 10 evaluable patients, CLR 131 achieved a 30% response rate. Patients received a single 30-minute infusion of CLR 131 at 25 mCi/m2, with the option for a second 25.0 mCi/m2 dose approximately 75 to 180 days later.5

In the RR MM cohort, there was 1 very good partial response (PR) and 2 PRs. Patients in this cohort averaged 5 lines of prior systemic therapies. All patients demonstrated at least stable disease.

As of October 1, CLOVER-1 had enrolled 20 patients in its MM arm (Figure). In patients with R/R MM, investigators will assess response to CLR 131 therapy by tracking M-protein and free light chain presence in urine and blood.

“We’ll continue to follow these biomarkers throughout treatment to recognize response,” Finn said. “If there is a reduction in these biomarkers either in the blood or urine, or if these biomarkers become undetectable, we know patients are achieving a partial remission or a complete remission.” She added that biomarkers that do not increase may also indicate that a patient is achieving stable disease (SD).

At the European Society for Medical Oncology Congress 2019, data were presented from the DLBCL cohort. For 6 patients who received 30-minute intravenous doses of CLR 131 (25 mCi/m2), investigators reported a 33% ORR, a 16.6% complete response rate (CR), and a 50% clinical benefit rate. Five of the 6 patients were refractory to at least 1 prior line of therapy.6

Investigators said CLR 131 showed activity against germinal center and activated DLBCL. In a patient for whom cytogenetics analysis was available, CLR 131 showed activity against c-Myc and BCL-2 mutation (single and dual-hit)—positive patients. The 1 patient who experienced a CR had a total reduction in tumor volume of >99% and remained in CR at >510 days post dosing. This patient was refractory to 2 prior treatment lines, which included rituximab (Rituxan), ifosfamide, carboplatin, and etoposide.

Figure. CLR 131 in Select B-cell Malignancies

The majority of adverse events (AEs) were hematologic in nature and predominantly grade 1/2, investigators said.

Current Offerings in MM

In MM, RT has traditionally been used to manage bone pain and improve quality of life.1 Current treatment choices for MM include immunomodulatory agents, proteasome inhibitors, monoclonal antibodies, and steroids.7 Additionally, alkylator, anthracycline, histone deacetylase inhibitor, and XP01 inhibitor classes each have 1 agent that is indicated for the treatment of MM. The most recent approval in MM came in July, when the FDA authorized the oral XP01 inhibitor selinexor (Xpovio) for use in combination with dexamethasone in patients with R/R MM who had received ≥4 prior therapies and whose disease was refractory to ≥2 proteasome inhibitors, ≥2 immunomodulatory agents, and an anti-CD38 monoclonal antibody.8

“MM is, fortunately, one of those disease types where it seems that more and more treatments are becoming available,” Finn said. Investigators hope CLR 131 will soon be one of them.

Adjusting Dosage

Earlier this year, investigators modified the dosing regimen based on the AE profile noted in a phase I study of patients with R/R MM.5 The dose alteration applies to 3 disease groups: MM, CLL, and DLBCL. Patients in these 3 cohorts will now receive CLR 131 at 15 mCi/m2 per week for 2 weeks, Finn said. Those with low grade lymphoma will also be treated with this dose.

The prevalence of thrombocytopenia was a factor in this decision, according to Finn. Thrombocytopenia presents relatively frequently in patients treated with CLR 131 and tends to be “more profound and a little more prolonged” than other cytopenias associated with the therapy, she said.

Prior Regimen Requirement

CLOVER-1 is open only to patients who have previously received SOC treatment for their respective B-cell malignancies. Those with MM are required to have had ≥2 prior regimens, which must include ≥1 approved proteasome inhibitor and ≥1 immunomodulatory agent, with or without maintenance therapy.2 Investigators will make an exception for patients with MM who are unable to tolerate these agents or were otherwise ineligible to receive them.

Patients with CLL/SLL, LPL, or MZL are expected to have had ≥2 prior regimens, consisting of chemotherapy; an approved anti-CD20 antibody, with or without maintenance therapy; and an approved targeted agent. Those with aggressive DLBCL and MCLs will need to have completed 1 prior line of therapy.2

It is intentional that relatively few earlier treatments are necessary for patients to qualify for CLOVER-1, Finn said. “Phase I and phase II studies are often thought of as last-line treatment options. We are trying to emphasize that providers should consider [CLOVER-1] in patients earlier than they may otherwise think to recommend an early phase study.”

CLR 131 need not be only a late-stage choice for patients with these B-cell lymphomas, Finn said: “[CLR 131] doesn’t have to be administered late, after many rounds of SOC therapy.” In MM, Finn said, “there is the option to use it earlier to give patients exposure to a different mechanism of action early in the course of treatment, or after they start to show that they may become refractory or unable to tolerate some of the drugs that we usually give in MM.”

References

  1. Talamo G, Dimaio C, Abbi KK, et al. Current role of radiation therapy for multiple myeloma. Front Oncol. 2015;5:40. doi: 10.3389/fonc.2015.00040.
  2. Study of CLR 131 in Relapsed or Refractory Select B-cell Malignancies (CLOVER-1). clinicaltrials.gov/ct2/show/NCT02952508. Updated July 23, 2019. Accessed October 3, 2019.
  3. Cellectar receives FDA fast track designation for CLR 131 in relapsed or refractory multiple myeloma [press release]. Florham Park, NJ: Cellectar Biosciences; May 13, 2019. cellectar.com/ news-media/press-releases/detail/206/cellectar-receives-fdafast-track-designation-for-clr-131. Accessed October 3, 2019.
  4. Cellectar received FDA fast track designation for CLR 131 in diffuse large B-cell lymphoma [press release]. Florham Park, NJ: Cellectar Biosciences; July 9, 2019. cellectar.com/news-media/press-releases/detail/211/cellectar-receives-fda-fasttrack-designation-for-clr-131. Accessed October 3, 2019.
  5. Cellectar reports positive top-line response rate of 30% from R/R multiple myeloma cohort in ongoing phase 2 study of CLR 131 [press release]. Florham Park, NJ: Cellectar Biosciences; February 25, 2019. globenewswire.com/ news-release/2019/02/25/1741555/0/en/Cellectar-Reports-Positive-Top-line-Response-Rate-of-30-from-R-RMultiple-Myeloma-Cohort-in-Ongoing-Phase-2-Study-ofCLR-131.html. Accessed October 3, 2019.
  6. Cellectar presents data from DLBCL cohort of its phase 2 CLOVER-1 study at the European Society for Medical Oncology (ESMO) Congress [press release]. Florham Park, NJ: Cellectar Biosciences; September 30, 2019. globenewswire. com/news-release/2019/09/30/1922485/0/en/CellectarPresents-Data-from-DLBCL-Cohort-of-its-Phase-2-CLOVER-1-Study-at-the-European-Society-for-Medical-Oncology-ESMO-Congress.html. Accessed October 3, 2019.
  7. Current FDA-approved medications. International Myeloma Foundation website. myeloma.org/multiple-myeloma-drugs. Updated August 15, 2019. Accessed October 2, 2019.
  8. Xpovio [prescribing information]. Newton, MA: Karyopharm Therapeutics, Inc.; 2019. www.accessdata.fda.gov/drugsatfda_docs/ label/2019/212306s000lbl.pdf. Accessed October 3, 2019.
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