Study of Chimeric Fibril-Reactive Monoclonal Antibody 11-1F4 in Patients With AL Amyloidosis

Phase Ia/Ib Study of Chimeric Fibril-Reactive Monoclonal Antibody 11-1F4 in Patients With AL Amyloidosis

The purpose of this study is to examine the tolerance, safety, pharmakinetics, and possible clinical benefit of the good manufacturing practice (GMP)-grade amyloid fibril-reactive chimeric (Ch) IgG1 mAb 11-1F4 in patients with amyloid light-chain (AL) amyloidosis. The phase 1a part will involve at least 3 patients and a maximum of 18 patients. The first patient will receive the starting dose of the antibody and, if tolerated, the following patients will each receive (if tolerated) progressively higher doses of the antibody. Patients in part 1a of the trial will receive only one infusion of the drug. Patients treated in the phase 1a part receive lower dosage which might not be effective. Once the maximal tolerated dosage is established during the phase 1a part, the investigators will accrue patients to the phase 1b part of the trial. Patients will receive 4 infusions, once each week for 4 weeks. Patients who were treated in the part 1a of the trial and showed no toxicity can be also treated in the part 1b of the trial. The first patient will receive the starting dose of the antibody and, if tolerated, the following patients will each receive (if tolerated) progressively higher doses of the antibody. When the investigators reach the maximum tolerated dose without toxicity, the investigators e will enroll another 4 patients to receive the same dose. If there are no toxicities, another 4 patients will be treated at the next dose level, and so forth. Patients treated in Phase 1b may receive lower dosages which might not be effective. The goal of Phase 1b is to establish the tolerance and possible beneficial effects of 11-1F4. If successful, treatment with this antibody would represent a novel approach in the care of individuals with AL amyloidosis.

Presently, treatment of patients with amyloid light chain (AL) amyloidosis is limited to reducing production of the amyloid-forming light-chain protein by giving conventional or high-dose (with stem cell transplant) anti-plasma cell chemotherapy, as used for patients with multiple myeloma. Although this approach has extended survival, the prognosis remains poor due to the persistence or progression of the amyloid deposits in vital organs, such as the heart or kidney. A different treatment strategy would be to attempt to reduce and/or eliminate these deposits. This study evaluates this by administering an anti-amyloid monoclonal antibody, 11-1F4. This compound has been shown to reduce/destroy this material in an experimental animal model of amyloidosis.

Administration of Chimeric Fibril-Reactive Monoclonal Anti-body 11-1F4: A 1-patient cohort will be infused with 0.5 mg/m2 of Ch 11-1F4 and, if tolerated, the doses in the next patients will be increased to 5, 10, 50, 100, 250, and finally, 500 mg/m2. All individuals will be evaluated prior to treatment, after infusion weekly for four weeks, as well as at 8 weeks.

Administration of Chimeric Fibril-Reactive Monoclonal Anti-body 11-1F4: Subjects will receive four weekly infusions of the monoclonal anti-body at Dose Level 1 (0.5 mg/m2). If tolerated, the doses in the next patients will be increased to 5, 10, 50, 100, 250, and finally, 500 mg/m2. When the highest tolerated dose is reached without toxicity in 2 patients, an additional 4 patients will be enrolled and infused at that dose. Escalation or de-escalation will continue until we have determined the highest dose level at which less than 2 patients experience toxicity. All individuals will be evaluated prior to each course of treatment, as well as at weeks 5, 8, and 12.

The MTD of a single application of Ch mAb 11-1F4 is defined as the highest safely-tolerated dose (mg/m2) where 0 patients experiences Dose Limiting Toxicity.

Amyloid-related organ response will be evaluated on the basis of the accepted criteria per consensus guidelines for the conduct and reporting of clinical trials in systemic light-chain amyloidosis, in patients who completed phase 1b.

This is designed to determine the pharmacokinetics of Ch mAb 11-1F4 when given as a single intravenous (i.v.) infusion (phase 1a) or as a series of four weekly intravenous infusions (phase 1b).

Phase 1a: 1, 2, 24 hours post start of infusion; then post-infusion week 1, 2, 3, 4, 8. Phase 1b: pretreatment, 1, 2, 24 hours post start of infusion; then post-infusion week 5, 8, 12.

This to obtain additional safety data of Ch mAb 11-1F4 when given as a single intravenous infusion (phase 1a) or as a series of four weekly intravenous infusions (phase 1b) by obtaining adverse event information for all subjects during active follow-up visits.

Inclusion Criteria: Patients must have a confirmed diagnosis of AL amyloidosis based on accepted clinical and laboratory criteria. Patients are greater than 21 years old. Female patients are not of child bearing potential or if they are of child bearing potential, they must not be pregnant or breast-feeding. Patients have a life expectancy greater than 3 months. Patients have an Eastern Cooperative Oncology Group (ECOG)-specified performance status of less than or equal to 3. Patients to be included are those with measurable, localized amyloid deposits (larynx, subcutaneous tissue, muscle, lung, lymph nodes) or clinically evident systemic disease (liver, kidney, heart, etc). Only patients with prior systemic therapy with relapsed/refractory disease are eligible, unless they have declined or are not eligible for high-dose melphalan and autologous hematopoietic stem cell transplant (HSCT) or any other standard therapy that has been known to be life-prolonging or life-saving. Patients have adequate organ function. Patients with cancer are eligible provided they meet specific criteria. Patients must provide signed, written, informed consent and be willing and able to comply with eligibility requirements, scheduled, visits, and follow-up studies. Exclusion Criteria: Non-AL amyloidosis. Renal failure (on dialysis). Females who are pregnant or breast-feeding. ECOG Performance Status greater than 3. Seriously limited cardiac, renal, or hepatic function. Uncontrolled infection or significant co-morbidity (e.g., uncontrolled diabetes, severe diarrhea).

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