Ascorbic Acid and Combination Chemotherapy in Treating Patients With Relapsed or Refractory Lymphoma

  • STATUS
    Recruiting
  • End date
    Mar 15, 2024
  • participants needed
    147
  • sponsor
    Mayo Clinic
Updated on 22 March 2021
platelet count
cancer
lymphoma
cytarabine
rituximab
monoclonal antibodies
measurable disease
HIV Infection
antiretroviral agents
direct bilirubin
etoposide
dexamethasone
combination chemotherapy
oxaliplatin
neutrophil count
carboplatin
gemcitabine
monoclonal antibody therapy
conjugated bilirubin
urine test
ifosfamide
salvage therapy
hiv disease

Summary

This randomized phase II trial studies how well ascorbic acid and combination chemotherapy work in treating patients with lymphoma that has come back (recurrent) or does not respond to therapy (refractory). 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 work better at treating lymphoma.

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 lymphomas not eligible for Arms A/B (peripheral T-cell lymphoma [PTCL], double-hit high grade, and Hodgkin lymphoma [HL]). (Arm C)

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 lymphoma. (Arm C)

EXPLORATORY OBJECTIVE:

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. (Correlative Research on blood and tumor tissue)

OUTLINE: Patients with DLBCL are randomized to Arms A or B. Patients with other lymphomas are assigned to Arm C.

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.

In all arms, 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.

Details
Condition Recurrent Hodgkin Lymphoma, Recurrent Lymphoma, Refractory Lymphoma, Refractory Diffuse Large B Cell Lymphoma, High Grade B-Cell Lymphoma With MYC and BCL2 or BCL6 Rearrangements, Recurrent Diffuse Large B-Cell Lymphoma, High Grade B-Cell Lymphoma With MYC and BCL2 or BCL6 Rearrangements, Recurrent Diffuse Large B-Cell Lymphoma, High Grade B-Cell Lymphoma With MYC and BCL2 or BCL6 Rearrangements, Recurrent Diffuse Large B-Cell Lymphoma, High Grade B-Cell Lymphoma With MYC and BCL2 or BCL6 Rearrangements, Recurrent Diffuse Large B-Cell Lymphoma, High Grade B-Cell Lymphoma With MYC and BCL2 or BCL6 Rearrangements, Recurrent Diffuse Large B-Cell Lymphoma, High Grade B-Cell Lymphoma With MYC and BCL2 or BCL6 Rearrangements, Recurrent Diffuse Large B-Cell Lymphoma, High Grade B-Cell Lymphoma With MYC and BCL2 or BCL6 Rearrangements, Recurrent Diffuse Large B-Cell Lymphoma, High Grade B-Cell Lymphoma With MYC and BCL2 or BCL6 Rearrangements, Recurrent Diffuse Large B-Cell Lymphoma, High Grade B-Cell Lymphoma With MYC and BCL2 or BCL6 Rearrangements, Recurrent Diffuse Large B-Cell Lymphoma, High Grade B-Cell Lymphoma With MYC and BCL2 or BCL6 Rearrangements, Recurrent Diffuse Large B-Cell Lymphoma
Treatment Rituximab, laboratory biomarker analysis, questionnaire administration, cisplatin, gemcitabine hydrochloride, cytarabine, etoposide, ifosfamide, carboplatin, Placebo, Dexamethasone, Oxaliplatin, Placebo Administration, Ascorbic acid
Clinical Study IdentifierNCT03418038
SponsorMayo Clinic
Last Modified on22 March 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Is your age greater than or equal to 18 yrs?
Gender: Male or Female
Do you have any of these conditions: Refractory Diffuse Large B Cell Lymphoma or Recurrent Hodgkin Lymphoma or Recurrent Diffuse Large B-Cell Lymphoma or Recurrent Lymphoma or High Grade ...?
Do you have any of these conditions: Refractory Diffuse Large B Cell Lymphoma or Recurrent Lymphoma or Refractory Lymphoma or High Grade B-Cell Lymphoma With MYC and BCL2 or BCL6 Rearrang...?
Do you have any of these conditions: Refractory Lymphoma or High Grade B-Cell Lymphoma With MYC and BCL2 or BCL6 Rearrangements or Recurrent Diffuse Large B-Cell Lymphoma or Recurrent Hod...?
Do you have any of these conditions: Refractory Lymphoma or High Grade B-Cell Lymphoma With MYC and BCL2 or BCL6 Rearrangements or Recurrent Hodgkin Lymphoma or Refractory Diffuse Large B...?
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 lymphoma patients of any type for which the recommended treatment includes one of the platinum-based regimens; of note, relapsed double-hit high grade lymphoma patients and relapsed 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
Provide written informed consent
If positive, the CD4 count must be > 400
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

Exclusion Criteria

Any of the following
Pregnant persons
Nursing persons
Persons of childbearing potential who are unwilling to employ adequate contraception
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
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
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; NOTE: Patients with calcium oxalate crystals on baseline urinalysis or a history of symptomatic calcium oxalate stones must be seen or have an e-consult by the Nephrology Stone Clinic and placed on a low oxalate diet (< 100 mg oxalate/day) prior to enrollment
Known paroxysmal nocturnal hemoglobinuria (PNH)
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