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2277 Cael-101 Is Well-Tolerated in AL Amyloidosis Patients Receiving Concomitant Cyclophosphamide-Bortezomib-Dexamethasone (CyborD): A Phase 2 Dose-Finding Study (NCT04304144)

Program: Oral and Poster Abstracts
Session: 653. Myeloma/Amyloidosis: Therapy, excluding Transplantation: Poster II
Hematology Disease Topics & Pathways:
Biological, antibodies, CRS, Therapies, Adverse Events, Clinically relevant
Sunday, December 6, 2020, 7:00 AM-3:30 PM

Jason Valent, MD1, John Silowsky, RN BSN2*, Michael R. Kurman, MD3, Eileen Daniel2*, Janet Jobes2*, Mark Harnett, MS4*, Margaret Ziola, MD2*, Jessica Roviwong2*, Sherry Fada1*, Michael Spector, BS2* and Susan B. Sobolov, PhD2*

1Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH
2Caelum Biosciences, Bordentown, NJ
3Michael Kurman Consulting, LLC, Upper Saddle River, NJ
4Caelum Biosciences, Stow, MA

Immunoglobulin light Chain (AL) amyloidosis is the most common form of systemic amyloidosis, accounting for approximately 70% of the diagnosed cases in developed countries. There are no approved treatments for AL amyloidosis, and currently autologous stem cell transplants and/or chemotherapy targeted to eradicate the underlying plasma-cell dyscrasia (PCD) to stop the production of misfolded light chains are used. No therapies are available to remove existing amyloid deposits, improve and/or reverse organ dysfunction.

CAEL-101 is a chimeric immunoglobulin G1 kappa isotype that reacts specifically with light chain fibrils, irrespective of their κ or λ isotype but, notably, not with the native forms. CAEL-101 was shown to bind to a cryptic epitope at the N-terminal of light chain proteins that adopt a non-native b-sheet structure, which is conserved in κ and λ mis-folded light chains. It is hypothesized that CAEL-101 will modify the disease course of AL amyloidosis by facilitating the removal of amyloid fibrils deposited in tissues. CAEL-101 was previously studied as monotherapy in an open label dose escalation Phase 1 study where it was shown to be safe, tolerable up to 500 mg/m2 and associated with an early organ response. No DLT were seen and the PK profile appeared not to reach linearity.

The current multicenter, open-label, sequential cohort, dose-selection study of CAEL-101 in Mayo Stage I, II and IIIa AL amyloidosis patients was to define the safety and tolerability of CAEL-101 in combination with Cyclophosphamide-Bortezomib-Dexamethasone (CyBorD) as the standard of care (SOC) PCD therapy during a 27-day treatment period and to determine the recommended dose for the subsequent Phase 3 studies. Patients had measurable hematologic disease, as defined by at least one of:

  1. involved/uninvolved free light chain (FLC) difference (dFLC) > 5mg/dL or
  2. FLC >5mg/dL with abnormal ratio or
  3. serum protein electrophoresis (SPEP) m- spike > 0.5 g/dL

Patients were seen in the clinic every week for 4 weeks to receive CAEL-101 2-HR IV infusions, and for safety and tolerability assessments. Subsequently, patients have been receiving CAEL-101 infusions approximately every other week.

Actual dose was determined by patient body surface area in meters squared. When administered on the same day, CAEL-101 was administered first before CyBorD chemotherapy.

The study employed a 3+3 dose escalation design, starting with a 500 mg/m2 dose. Patients were followed for dose-limiting toxicities (DLTs). The DLT observation period for the first cohort was through 14 days following the first infusion. For subsequent cohorts, this was through 27 days. At least 3 patients were enrolled in each dose cohort. Enrollment into a new cohort with the next higher dose of CAEL-101 did not begin until the DLT observation period had been completed for the last patient enrolled in the previous cohort, with further dosing cohorts at 750 and 1000 mg/m2. Safety assessment included vital signs, physical examinations, electrocardiograms (ECGs), clinical laboratory parameters (hematology, serum chemistry, urinalysis), and TEAEs. The pharmacokinetic (PK) profile of CAEL-101 was also assessed.

The 13 patients averaging 65.2 years (range 47.6 to 79.6 years). The majority were male (76.9%), white (84.6%), and non-Hispanic (100%). Mayo staging I (7.7%), II (69.2%), and III (23.1%) reflected a wide range of disease severity in the patients enrolled. All patients were treated successfully through their 4th dose, the highest (1000 mg/m2) cohort enrolling 6 patients. No DLT was observed, and CAEL-101 was well-tolerated by all patients. The most common TEAEs were diarrhea and nausea (each 30.8%). Dose-normalized PK concentrations were best described by a linear two-compartment model, with terminal half-life of 28 days.

This study demonstrated that CAEL-101 at doses up to 1000 mg/m2, given with CyBorD, was well-tolerated in the AL amyloidosis population. Two Phase 3 efficacy/safety studies, one enrolling Mayo Stage IIIa and the other Stage IIIb patients, have been initiated, and based on the findings from this Phase 2 study, the 1000 mg/m2 dose of CAEL-101 is being used for treatment in those studies.

Disclosures: Valent: Takeda Pharmaceuticals: Other: Teaching, Speakers Bureau; Celgene: Other: Teaching, Speakers Bureau; Amgen Inc.: Other: Teaching, Speakers Bureau. Silowsky: Caelum Biosciences: Current Employment, Current equity holder in private company. Kurman: Caelum Biosciences: Consultancy. Daniel: Caelum Biosciences: Current Employment, Current equity holder in private company. Jobes: Caelum Biosciences: Current Employment, Current equity holder in private company. Harnett: Caelum Biosciences: Consultancy, Current equity holder in private company. Ziola: Caelum Biosciences: Consultancy. Roviwong: Caelum Biosciences: Current Employment, Current equity holder in private company. Spector: Caelum Biosciences: Current Employment, Current equity holder in private company. Sobolov: Caelum Biosciences: Current Employment, Current equity holder in private company.

*signifies non-member of ASH