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

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)

TERTIARY 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. (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 courses 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 courses 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 courses 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 courses 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 courses in the absence of disease progression or unacceptable toxicity. Patients
who achieve MR or SD after 2 courses 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.

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 lymphoma patients of any type, other than
those eligible for Arms A/B, 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 rituximab,
cisplatin, cytosine arabinoside, dexamethasone (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

- Patients known to be human immunodeficiency virus (HIV) positive must be stable and
currently receiving antiretroviral therapy with a CD4 count > 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

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

- 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; NOTE: Patients with calcium
oxalate crystals on baseline urinalysis or a history of symptomatic calcium oxalate
stones must be seen by the Nephrology Stone Clinic and placed on a low oxalate diet (<
100 mg oxalate/day) prior to enrollment

- Known paroxysmal nocturnal hemoglobinuria (PNH)