High Dose Ascorbic Acid and Low Dose Melphalan in Treating Patients with Relapsed and Refractory Multiple Myeloma

Status: Active

Description

This phase I trial studies the best dose and side effects of high dose ascorbic acid when given together with low dose melphalan in treating patients with multiple myeloma that has come back and does not respond to treatment. High doses of ascorbic acid may kill the cancer cells (myeloma cells in the bone marrow), while preserving normal cells. Drugs used in chemotherapy, such as melphalan, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving high dose ascorbic acid and low dose melphalan may work better in treating patients with multiple myeloma compared to low dose melphalan without high dose ascorbic acid.

Eligibility Criteria

Inclusion Criteria

  • Subject has provided informed consent
  • Patients who have been previously treated with 3 lines of therapy, i.e. proteasome inhibitors, immuno-modulatory agents such as lenalidomide and monoclonal antibodies such as daratumumab, and have progressed within past 6 months. Participants with previous failed autologous transplant and progressed within 6 months after autologous transplant * Note: Induction with or without hematopoietic stem cell transplant and with or without maintenance therapy is considered a single regimen
  • Patients have failed treatment with, are intolerant to or are not candidates for available therapies that are known to confer clinical benefit to patients with relapsed and refractory multiple myeloma (MM)
  • Subjects must have measurable disease (as determined by the central lab), including at least one of the criteria below: * M-protein quantities >= 0.5 g/dl by serum protein electrophoresis (SPEP) or * >= 200 mg/24 hour urine collection by urine protein electrophoresis (UPEP) or * Serum free light chain levels > 100 mg/L (milligrams/liter involved light chain) and an abnormal kappa/lambda ratio in patients without detectable serum or urine m-protein or * 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 ** Non-secretory participants are eligible provided the participant has >= 20% bone marrow plasmacytosis OR multiple (>= 3) plasmacytomas or lesions on magnetic resonance imaging (MRI) at the time of diagnosis or study enrollment, OR the presence of lesions (>= 3) on positron emission tomography (PET)/computed tomography (CT) scan
  • Absolute neutrophil count (ANC) >= 1.0 x 10^9/L without growth factor support for 7 days (14 days if pegfilgastrim)
  • Platelets (plt) >= 50 x 10^9/L without transfusion for 7 days
  • Potassium within normal limits or correctable with supplements
  • Aspartate aminotransferase (AST/serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT/serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x 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
  • Ejection fraction by echocardiography (ECHO) or multigated acquisition scan (MUGA) of >= 40% performed
  • Participants must have adequate pulmonary function studies (PFTs), >= 50% of predicted on mechanical aspects (forced expiratory volume in 1 second [FEV1], forced vital capacity [FVC]) and diffusion capacity (DLCO) >= 50% of predicted (adjusted for hemoglobin). If the participant is unable to complete PFTs due to disease-related pain or other circumstances that make it difficult to reliably perform PFTs, documentation of pulmonary function adequate for transplant will occur via a CT scan without evidence of major pulmonary disease, and arterial blood gas results
  • Participants must have a performance status of 0-2 based on Eastern Cooperative Oncology Group (ECOG) criteria. Participants with poor performance status (3-4) based solely on bone pain will be eligible, provided there is documentation to verify this
  • Negative serum or urine pregnancy test (sensitivity of at least 25 mIU/mL) at screening

Exclusion Criteria

  • Prior allogeneic transplant
  • 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 that he/she has not had any chemotherapy within 365 days of study entry AND that life expectancy exceeds 5 years at the time of study entry
  • Participants must not have life-threatening comorbidities
  • History or evidence of myeloma associated with immunodeficiency states (e.g.: hereditary immune deficiency, human immunodeficiency virus [HIV], organ transplant or leukemia)
  • Known human immunodeficiency virus (HIV) disease (requires negative test for clinically suspected HIV infection)
  • Evidence of central nervous system (CNS) myeloma
  • 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 glucose-6-phosphate dehydrogenase (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

Locations & Contacts

Iowa

Iowa City
University of Iowa / Holden Comprehensive Cancer Center
Status: Active
Contact: Yogesh S. Jethava
Phone: 319-384-9067
Email: Yogesh-jethava@uiowa.edu

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To determine the safety and tolerability of high dose ascorbic acid in combination with low dose melphalan in relapsed refractory multiple myeloma patients.

SECONDARY OBJECTIVES:

I. Determine the rate of minimal residual disease (MRD) negativity 30 days after treatment with a high dose ascorbic acid in combination with a reduced dose of melphalan.

II. Determine tumor response using the International Myeloma Working Group (IMWG) criteria.

III. Categorize and quantify adverse events compared to historical control.

IV. Determine oxidative stress parameters in plasma during the course of treatment.

OUTLINE: This is a dose-escalation study of ascorbic acid.

Patients receive a test dose of ascorbic acid intravenously (IV) at baseline. Patients then receive low dose melphalan IV on days 1 and 4 and high dose ascorbic acid IV over 30-180 minutes on days 1, 2, 4, and 5 in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up once weekly for up to 11 weeks, every 3 months for up to 2 years, and then periodically for up to 3 years.

Trial Phase & Type

Trial Phase

Phase I

Trial Type

Treatment

Lead Organization

Lead Organization
University of Iowa / Holden Comprehensive Cancer Center

Principal Investigator
Yogesh S. Jethava

Trial IDs

Primary ID 201804754
Secondary IDs NCI-2019-00738
Clinicaltrials.gov ID NCT03602235