High Dose Ascorbic Acid for Plasma Cell Disorders

Study Overview
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Brief Summary
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This is a Phase I single-arm open-label clinical study primarily assessing the safety and secondarily, the relative efficacy of low dose melphalan + high dose ascorbate acid (HDAA) in relapsed refractory patients with multiple myeloma.

Detailed Description
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This is a phase 1 study for patients with relapsed refractory multiple myeloma. Patients will receive a 15-gram test dose, and a maximum of 3 cycles, each composed of 4 doses of high-dose ascorbic acid (HDAA) and 2 doses of melphalan. This study will enroll 9 patients with relapsed refractory multiple myeloma. The starting dose of ascorbic acid will be 50 grams. Using a 3+3 dose escalation, the dose will potentially increase to 75 grams then 100 grams.

Official Title
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High Dose Ascorbic Acid (HDAA) in Patients With Plasma Cell Disorders

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Other: Ascorbate
* Drug: Melphalan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject has provided informed consent. Diagnosis of multiple myeloma per IMWG criteria(26) Patients must have progressive disease following 3 or more prior lines of therapy. Prior treatment must include a proteasome inhibitor, an immunomodulatory agent (IMiD), and an anti-CD38 monoclonal antibody. Patients must not be candidates for regimens known to provide clinical benefit in relapsed or refractory multiple myeloma based on the investigator's judgement. If a patient declines such therapy, this must be recorded in the study files. 4. Subjects must have measurable disease, including at least one of the criteria below: SPEP demonstrating M-protein quantities ≥ 0.5 g/dl UPEP demonstrating monoclonal protein ≥ 200 mg/24hr Involved serum free light chain levels > 100 mg/L and an abnormal kappa/lambda (κ/λ)ratio For patients with immunoglobulin class A (IgA) myeloma whose disease can only be reliably measured by quantitative immunoglobulin measurement, a serum IgA level ≥ 500 mg/dl will qualify as measurable disease Non-secretory participants are eligible provided the participant has > 20% bone marrow plasmacytosis Adequate organ function: Absolute neutrophil count (ANC) ≥ 1.0 x 10^9/L without growth factor support for 7 days Platelets (plt) ≥ 50 x 10^9/L without transfusion for 7 days. Hemoglobin ≥ 8.0 g/dl, transfusion support permitted Aspartate aminotransferase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) ≤ 3.0x upper limit of normal (ULN) Serum bilirubin ≤ 1.5 x ULN Estimated serum creatinine clearance of ≥ 45 mL/min using the Cockcroft-Gault equation or directly calculated from the 24-hour urine collection method. International normalized ratio (INR) < 1.5 x ULN and partial thromboplastin time (PTT) < 1.5 x ULN Left Ventricular Ejection Fraction by ECHO or MUGA of ≥ 40%. Participants must have a performance status of 0-2 based on ECOG criteria. For women of child bearing potential negative serum or urine pregnancy test (sensitivity of at least 25 mIU/mL) at screening Exclusion Criteria Known hypersensitivity or allergy to ascorbic acid or melphalan Participants must not have a concurrent malignancy unless it can be adequately treated by non- chemotherapeutic intervention. Participants may have a history of prior malignancy, provided they have not had any chemotherapy within 365 days of study entry AND their life expectancy exceeds 5 years with respect to the concurrent malignancy at the time of study entry. Participants must not have life-threatening comorbidities. Known human immunodeficiency virus(HIV) disease (requires negative test for clinically suspected HIV infection). Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, recent (within 6 months) myocardial infarction, uncontrolled or symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, uncontrolled hypertension on appropriate therapy or psychiatric illness/social situations that would limit compliance with study requirements. Concurrent use of Coumadin (warfarin) Patients with G6PD deficiency Patients with a history of oxalate renal stones or a known history of multiple renal stones Diabetic patients who rely on a glucometer to dose insulin as ascorbate can interfere with glucometer readings

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low dose melphalan + high dose ascorbate acid (HDAA)<br>Patients will receive a test dose of 15g of HDAA prior to starting treatment dose. This will be mainly to rule out allergic reactions. HDAA + Melphalan: HDAA on day 1 and day 4 in combination with melphalan 12.5 mg/m2, followed by 2 additional doses of HDAA on day 2 and day 5. A 3 + 3 cohort method will be used for this study. After successfully completing the test dose, subjects will receive 50gms, 75gms and 100gms of ascorbate per infusion in 3 different cohorts. Dose modifications are not made for weight or body surface area. | Other: Ascorbate<br>* Ascorbate is in the vitamin drug class<br>* Other names: Ascorbate Acid; Ascorbic Acid for Injection, USP;Drug: Melphalan<br>* Melphalan is an alkylating agent coupled to an amino acid<br>* Other names: L-phenylamine mustard; L-PAM; L-Sarcolysin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of treatment related adverse events as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 | Adverse events occuring within the DLT assessment window which do not resolve in less than 72 hours and are not clearly and incontrovertibly due to extraneous causes. | First day of treatment through 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of minimal residual disease (MRD) negativity through bone marrow testing and imaging | MRD will be determined by highly sensitive, eight color flow on bone marrow sample. Functional imaging, such as PET scan and MRI will also be performed to assess the disease status. | Through 28 days after the end of treatment | 
| Overall response rate based on International Myeloma Working Group (IMWG) criteria | Response to treatment will be assessed by IMWG criteria. | Through 24 months after the end of treatment | 
| Categorize and quantify adverse events compared to historical control | The number and severity of all adverse events will be summarized by simple descriptive statistics and compared to a historical control. | Up to 24 months following the end of treatment for the last patient | 
| Oxidative stress parameters in plasma through blood testing | Blood will be drawn and serum iron, TIBC, serum ferritin and transferrin saturation levels tested. | Through 24 months after the end of treatment |