Myelodysplastic Syndrome Clinical Trial

Ascorbic Acid and Combination Chemotherapy for the Treatment of Relapsed or Refractory Lymphoma or Clonal Cytopenia of Undetermined Significance

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) or clonal cytopenia of undetermined significance. 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.

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Full 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)

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.

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)

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.

Arm A: 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: 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: 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 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.

In Arms A, B, and C, patients who achieve complete response (CR), partial response (PR) or MR may undergo stem cell transplantation.

After completion of study treatment, patients are followed up every 3 months, then every 6 months after progressive disease for up to 2 years.

View Eligibility Criteria

Eligibility Criteria

Inclusion Criteria:

Biopsy-proven relapsed or refractory lymphomas; relapsed is defined as a relapse that occurred after having a response to the last therapy that lasted > 6 months; refractory is no response or relapse within 6 months; previous biopsies < 6 months prior to treatment on this protocol will be acceptable

NOTE: Arms A/B - relapsed or refractory DLBCL within 24 months from the end of anthracycline-based therapy; no prior salvage therapy; patients can have received radiation therapy as part of initial treatment but not specifically for relapse
NOTE: Arm C patients include relapsed or refractory lymphoma patients of any type for which the recommended treatment includes one of the platinum-based regimens; of note, relapsed or refractory double-hit high grade lymphoma patients and relapsed or refractory Hodgkin lymphoma patients will be enrolled in Arm C; there is no limit on the number of prior therapies for Arm C patients; the patient must be eligible for a platinum-based regimen and must not have received the same regimen in the past without responding

Measurable or assessable disease: measurable disease is defined as measurable by computed tomography (CT) (dedicated CT or the CT portion of a positron emission tomography [PET]/CT) or magnetic resonance imaging (MRI): to be considered measurable, there must be at least one lesion that has a single diameter of >= 1.5 cm

NOTE: Skin lesions can be used if the area is >= 1.5 cm in at least one diameter and photographed with a ruler; patients with assessable disease by PET are also eligible as long as the assessable disease is biopsy proven lymphoma
Arms A/B - eligible for treatment with ifosfamide, carboplatin, and etoposide (+/- rituximab)

Arm C eligible for treatment with one of the following standard, every 3 week, platinum-based salvage regimens (with or without monoclonal antibody as appropriate for the disease):

Ifosfamide/carboplatin/etoposide (ICE) or rituximab/ifosfamide/carboplatin/etoposide (RICE);
Cisplatin, cytarabine (cytosine arabinoside), dexamethasone (DHAP) or RDHAP;
Gemcitabine hydrochloride (gemcitabine), dexamethasone, cisplatin (GDP) or rituximab, gemcitabine, dexamethasone, cisplatin (RGDP);
Gemcitabine and oxaliplatin (GemOx) or rituximab, gemcitabine and oxaliplatin (RGemOx);
Oxaliplatin, cytosine arabinoside, dexamethasone (OAD) or rituximab, oxaliplatin, cytosine arabinoside, dexamethasone (ROAD)
Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2
Hemoglobin >= 8.0 g/dL (may transfuse to meet this requirement), obtained =< 14 days prior to registration
Absolute neutrophil count (ANC) >= 1500/mm^3, obtained =< 14 days prior to registration
Platelet count >= 75000/mm^3, obtained =< 14 days prior to registration
Total bilirubin =< 2 x upper limit of normal (ULN) (if > 2 x ULN direct bilirubin is required and should be =< 1.5 x ULN), obtained =< 14 days prior to registration
Alanine aminotransferase (ALT) and aspartate transaminase (AST) =< 3 x ULN (=< 5 x ULN for patients with liver involvement), obtained =< 14 days prior to registration
Creatinine =< 1.6 mg/dL; if over 1.6 then the calculated creatinine clearance must be >= 55 ml/min using the Cockcroft-Gault formula, obtained =< 7 days prior to registration

Negative pregnancy test done =< 7 days prior to registration, for persons of childbearing potential only

NOTE: If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required

Human immunodeficiency virus (HIV) test done =< 14 days prior to registration

If positive, the CD4 count must be > 400
Provide written informed consent
Willingness to have a central venous line (peripherally inserted central catheter [PICC] or PORT)
Willingness to provide mandatory blood specimens for correlative research
Willingness to provide mandatory tissue specimens for correlative research
Willingness to return to enrolling institution for follow-up (during the active monitoring phase of the study)
Willingness to follow the requirements of the intravenous ascorbic acid program schedule
ARM D: Patients who had a diagnosis of CCUS with one or more TET2 mutations or TET2 mutations with concurrent splicing genes mutations (SRSF2, U2AF1, SF3B1, and ZRSR2) or epigenetic regulator mutations (DNMT3A, EZH2, IDH1, IDH2). CCUS diagnosis being defined based on the absence of definitive morphologic evidence of hematologic neoplasms from bone marrow biopsy evaluation combined with evidence of pathogenic myeloid somatic mutation with a variant allele frequency (VAF) of at least 2% using our institution's next generation sequencing (NGS) panel (OncoHeme, Mayo Clinic)
ARM D: ECOG performance status (PS) 0, 1 or 2

ARM D: Patients must meet at least 1 of these 3 laboratory criteria to be enrolled:

Hemoglobin =< 10g/dL (obtained =< 7 days prior to registration)
Absolute neutrophil count (ANC) =< 1000/mm^3 (obtained =< 7 days prior to registration)
Platelet count =< 100,000/mm^ 3 (obtained =< 7 days prior to registration)
ARM D: Total bilirubin =< 2 x ULN (if > 2 x ULN direct bilirubin is required and should be =< 1.5 x ULN) (obtained =<7 days prior to registration)
ARM D: Alanine aminotransferase (ALT) and aspartate transaminase (AST) =< 3 x ULN (=< 5 x ULN for patients with liver involvement) (obtained =<7 days prior to registration)
ARM D: Creatinine =< 1.6 mg/dL (obtained =<7 days prior to registration). If > 1.6, then the Calculated creatinine clearance must be >= 55 ml/min using the Cockcroft-Gault formula
ARM D: Negative pregnancy test, for persons of childbearing potential only (obtained =< 7 days prior to registration). NOTE: If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
ARM D: Provide written informed consent
ARM D: Willingness to have a central venous line (PICC or PORT)
ARM D: Willingness to provide mandatory blood specimens for correlative research
ARM D: Willingness to return to enrolling institution (MCR) for follow-up (during the active monitoring phase of the study)
ARM D: Willingness to follow the requirements of the intravenous ascorbic acid program schedule

Exclusion Criteria:

Any of the following:

Pregnant persons
Nursing persons
Persons of childbearing potential who are unwilling to employ adequate contraception
Any therapy =< 2 weeks prior to registration; NOTE: Exception: patients on ibrutinib or corticosteroids (any dose) may continue therapy up until the new regimen has started at investigator discretion; corticosteroids can be tapered to lowest possible dose after start of treatment at investigator discretion. Exception: Palliative radiation is allowed
Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, pulmonary congestion or pulmonary edema, clinical dehydration, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
Receiving any other investigational agent which would be considered as a treatment for the lymphoma

Other active malignancy than lymphoma

NOTE: If there is a history of prior malignancy, they must not be receiving other specific treatment for their cancer that could interfere with this protocol therapy; patients on hormonal therapy for treated breast or prostate cancer are permitted if they meet other eligibility criteria; patients with non-melanotic skin cancer may enroll
History of myocardial infarction =< 6 months, or current symptomatic congestive heart failure or left ventricular ejection fraction (LVEF) < 40% or with > grade 2 diastolic dysfunction, with no symptoms or signs of heart failure
Known G6PD (glucose-6-phosphate dehydrogenase) deficiency (below lower limit of normal)
Patients with active central nervous system (CNS) lymphoma or active cerebrospinal fluid (CSF) involvement with malignant cells requiring CNS-specific therapy with IV or intrathecal (IT) methotrexate (MTX); Note: Patients with any prior CNS lymphoma (parenchymalor leptomeningeal) MUST be in complete remission (CR) in those compartments without any maintenance therapy required
Patients with uncontrolled or symptomatic kidney stones
Known paroxysmal nocturnal hemoglobinuria (PNH)
ARM D: Bona-fide hematological neoplasm

ARM D: Any of the following because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects:

Pregnant persons
Nursing persons
Persons of childbearing potential who are unwilling to employ adequate contraception
ARM D: Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens
ARM D: Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, pulmonary congestion or pulmonary edema, clinical dehydration, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
ARM D: History of myocardial infarction =< 6 months, or current symptomatic congestive heart failure or known LVEF < 40% or with > grade 2 diastolic dysfunction, with no symptoms or signs of heart failure
ARM D: Patients with uncontrolled or symptomatic kidney stones
ARM D: Known paroxysmal nocturnal hemoglobinuria (PNH)
ARM D: Known G6PD (glucose-6-phosphate dehydrogenase) deficiency (below lower limit of normal)

Study is for people with:

Myelodysplastic Syndrome

Phase:

Phase 2

Estimated Enrollment:

147

Study ID:

NCT03418038

Recruitment Status:

Recruiting

Sponsor:

Mayo Clinic

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There are 5 Locations for this study

See Locations Near You

Mayo Clinic in Arizona
Scottsdale Arizona, 85259, United States More Info
Clinical Trials Referral Office
Contact
855-776-0015
[email protected]
Craig B. Reeder, M.D.
Principal Investigator
Mayo Clinic in Florida
Jacksonville Florida, 32224, United States More Info
Clinical Trials Referral Office
Contact
855-776-0015
[email protected]
Taimur Sher, M.D.
Principal Investigator
University of Iowa/Holden Comprehensive Cancer Center
Iowa City Iowa, 52242, United States More Info
Umar Farooq
Contact
[email protected]
Umar Farooq
Principal Investigator
Mayo Clinic in Rochester
Rochester Minnesota, 55905, United States More Info
Clinical Trials Referral Office
Contact
855-776-0015
[email protected]
Thomas E. Witzig, M.D.
Principal Investigator
Mayo Clinic Health System-Franciscan Healthcare
La Crosse Wisconsin, 54601, United States More Info
Traci Heaney
Contact
608-392-6810
[email protected]
Traci Heaney
Principal Investigator

How clear is this clinincal trial information?

Study is for people with:

Myelodysplastic Syndrome

Phase:

Phase 2

Estimated Enrollment:

147

Study ID:

NCT03418038

Recruitment Status:

Recruiting

Sponsor:


Mayo Clinic

How clear is this clinincal trial information?

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