Trials / Recruiting

RecruitingNCT03418038

Ascorbic Acid and Chemotherapy for the Treatment of Relapsed or Refractory Lymphoma, CCUS, and Chronic Myelomonocytic Leukemia

Phase2 Trial of High Dose Intravenous Ascorbic Acid as an Adjunct to Salvage Chemotherapy in Relapsed/ Refractory Lymphoma, Patients With Clonal Cytopenia of Undetermined Significance, and Chronic Myelomonocytic Leukemia

Status: Recruiting
Phase: Phase 2
Study type: Interventional
Enrollment: 80 (estimated)

Sponsor: Mayo Clinic · Academic / Other
Sex: All
Age: 18 Years
Healthy volunteers: Not accepted

Summary

This phase II trial studies the effect of ascorbic acid and combination chemotherapy in treating patients with lymphoma that has come back (recurrent) or does not respond to therapy (refractory), clonal cytopenia of undetermined significance and chronic myelomonocytic leukemia (CMML). Ascorbic acid may make cancer cells more sensitive to chemotherapy. Drugs used in chemotherapy, 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 ascorbic acid and combination chemotherapy may kill more cancer cells. Arms A, B, C, and D are closed to enrollment.

Detailed description

PRIMARY OBJECTIVES: I. To determine the overall response rate (ORR) at the end of 2 cycles for intravenous (IV) ascorbic acid (AA) added to standard salvage therapy compared to standard salvage therapy plus normal saline in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who have relapsed within the first 24 months of end of their therapy. \[Arms A versus (vs) B\] II. To determine the ORR at the end of 2 cycles of AA plus standard salvage chemotherapy in patients with other types of relapsed/refractory lymphomas not eligible for Arms A/B \[peripheral T-cell lymphoma (PTCL), double-hit high grade, and Hodgkin lymphoma (HL)\]. (Arm C) III. To assess the hematological response rate to treatment with high dose intravenous ascorbic acid (IV AA) for clonal cytopenia of undetermined significance (CCUS) patients. (Arm D) IV. To assess the hematological response rate to treatment with high dose intravenous ascorbic acid (IV AA) for CCUS patients. (Arm E) SECONDARY OBJECTIVES: I. To compare the adverse event profile of IV AA added to salvage therapy versus salvage therapy plus IV saline in patients with DLBCL using both the Common Terminology Criteria for Adverse Events (CTCAE) and Patient-Reported Outcomes (PRO)-CTCAE. (Arms A and B) II. To compare the progression-free survival, overall survival, clinical benefit rate (those not progressing), and percentage (%) transplant eligible patients proceeding to transplant of AA added to salvage therapy versus salvage therapy plus IV saline in patients with DLBCL. (Arms A and B) III. To compare the ORR at the end of 4 cycles for those with minor response/stable disease at the end of cycle 2 who proceed to receive the additional 2 cycles of rituximab, dexamethasone, cytarabine and cisplatin (RDHAP) with either AA or normal saline (NS) as previously assigned. (Arms A and B) IV. To evaluate the adverse event profile, rate of febrile neutropenia, overall survival, progression-free survival, and clinical benefit rate of AA added to salvage therapy in patients with relapsed/refractory lymphoma. (Arm C) V. To assess safety/tolerability, transfusion dependency (TD), progression-free survival (PFS), and overall survival (OS) for CCUS patients receiving high dose IV AA. (Arm D) VI. To define CR, complete cytogenetic remission, partial remission, marrow response, and clinical benefit response rates. (Arm E) VII. To determine clinical benefit response rates of erythroid response, platelet response, neutrophil response, spleen response and symptom response as adjudicated by the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) total symptom scoring system. (Arm E) EXPLORATORY OBJECTIVES: I. Will include baseline AA levels \[at Mayo Clinic Research (MCR)\] and staining of pre/post treatment biopsies for markers of oxidative stress generation and deoxyribonucleic acid (DNA) methylation. (Arms A, B, and C Correlative Research on blood and tumor tissue) IIa. To assess TET2 activity at baseline, weeks 12, 20, and 52. (Arm D correlative research) IIb. To assess the association between using AA and the hydroxymethylation and methylation status (gene-specific and global changes in 5mC/5hmC level) at baseline and weeks 20 and 52. (Arm D correlative research) IIc. To assess the association between using IV AA and endothelial dysfunction (at baseline, weeks 20, and 52). (Arm D correlative research) IId. To assess the association between using IV AA and the inflammation markers. (Arm D correlative research) IIe. To assess the association between using IV AA and molecular response including clonal dynamics \[new mutations and variant allele frequency (VAF)\] (at baseline, weeks 20, and 52). (Arm D correlative research) III. Correlative studies will assess impact on: IIIa. Somatic mutational allele burdens after 4 cycles of therapy; IIIb. DNA methylation and hydroxymethylation after 4 cycles of therapy; IIIc. Inflammatory cytokines; IIId. Colony forming assay growth and differentiation; IIIe. Methylation at the single colony level; IIIf. Single cell methylation, transcription, and somatic mutations. (Arm E correlative research) OUTLINE: Patients with DLBCL are randomized to Arms A or B. Patients with other lymphomas are assigned to Arm C. Patients with CCUS are assigned to Arm D. Patients with TET2 mutant CMML are assigned to ARM E. Arm A \[Closed to enrollment\]: Patients receive ascorbic acid IV on days 1, 3, 5, 8, 10, 12, 15, 17, and 19, and rituximab intravenously (IV), ifosfamide IV, carboplatin IV and etoposide IV on days 1-3. Patients who achieve minor response (MR) or stable disease (SD) after 2 cycles may receive rituximab IV or PO, cisplatin IV or PO, cytarabine IV or PO, and dexamethasone IV or PO. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. ARM B \[Closed to enrollment\]: Patients receive placebo (normal saline) IV on days 1, 3, 5, 8, 10, 12, 15, 17, and 19, and rituximab intravenously IV, ifosfamide IV, carboplatin IV and etoposide IV on days 1-3. Patients who achieve MR or SD after 2 cycles may receive rituximab IV or PO, cisplatin IV or PO, cytarabine IV or PO, and dexamethasone IV or PO. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. ARM C \[Closed to enrollment\]: Patients receive ascorbic acid IV on days 1, 3, 5, 8, 10, 12, 15, 17, and 19. Patients also receive ifosfamide, carboplatin, and etoposide IV or PO, or cisplatin, cytarabine, and dexamethasone IV or PO, or gemcitabine hydrochloride, dexamethasone, and cisplatin IV or PO, or gemcitabine hydrochloride and oxaliplatin IV or PO, or oxaliplatin, cytarabine, and dexamethasone IV or PO according to standard regimen schedule. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients who achieve MR or SD after 2 cycles may switch to an alternative chemotherapy regimen. ARM D: Patients receive ascorbic acid IV three times a week (TIW). Treatments repeat every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. ARM E \[Closed to enrollment\]: Patients receive ascorbic acid IV on days 1, 3 and 5 and decitabine IV over 1 hour on days 1-5. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients with stable disease after 12 cycles may continue decitabine with or without ascorbic acid as long as clinically appropriate. Patients may also take vitamin C PO on days 6-28. In Arms A, B, and C, patients who achieve complete response (CR), partial response (PR) or MR may undergo stem cell transplantation. Patients additionally, undergo blood sample collection, core needle biopsy, bone marrow aspiration and biopsy, echocardiography (ECHO), positron emission tomography (PET)/ computed tomography (CT) or magnetic resonance imaging (MRI) throughout study. Patients in ARM D and E undergo peripherally inserted central catheter (PICC) or portacath placement prior to starting treatment, blood sample collection, bone marrow aspiration and biopsy throughout study. After completion of study treatment, patients are followed up every 3 months, then every 6 months after progressive disease for up to 2 years.

Conditions

Interventions

Type	Name	Description
DIETARY_SUPPLEMENT	Ascorbic Acid	Given IV
DRUG	Carboplatin	Given IV or PO
DRUG	Cisplatin	Given IV or PO
DRUG	Cytarabine	Given IV or PO
DRUG	Dexamethasone	Given IV or PO
DRUG	Etoposide	Given IV or PO
DRUG	Gemcitabine Hydrochloride	Given IV or PO
DRUG	Ifosfamide	Given IV or PO
OTHER	Laboratory Biomarker Analysis	Correlative studies
DRUG	Oxaliplatin	Given IV or PO
OTHER	Placebo Administration	Given normal saline IV
OTHER	Questionnaire Administration	Ancillary studies
BIOLOGICAL	Rituximab	Given IV
DRUG	Decitabine	Given IV
PROCEDURE	Biospecimen Collection	Undergo blood sample collection
PROCEDURE	Core Biopsy	Undergo core needle biopsy
PROCEDURE	Bone Marrow Aspiration	Undergo bone marrow aspiration and biopsy
PROCEDURE	Bone Marrow Biopsy	Undergo bone marrow aspiration and biopsy
PROCEDURE	Echocardiography	Undergo ECHO
PROCEDURE	Positron Emission Tomography	Undergo PET/CT
PROCEDURE	Magnetic Resonance Imaging	Undergo MRI
PROCEDURE	Central Venous Cannula Insertion	Undergo PICC placement
PROCEDURE	Portacath Placement	Undergo portacath placement
PROCEDURE	Computed Tomography	Undergo PET/CT

Timeline

Start date: 2018-03-23
Primary completion: 2031-02-22
Completion: 2033-11-02
First posted: 2018-02-01
Last updated: 2026-04-16

Locations

4 sites across 1 country: United States

Regulatory

FDA-regulated drug study

Source: ClinicalTrials.gov record NCT03418038. Inclusion in this directory is not an endorsement.