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

• Status: Recruiting
• Trial end date: 2024-03-15
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Mayo Clinic
• Collaborator: National Cancer Institute (NCI)
• Treatments: Antibodies; Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Ascorbic Acid; BB 1101; Carboplatin; Cisplatin; Cytarabine; Dexamethasone; Dexamethasone acetate; Etoposide; Etoposide phosphate; Gemcitabine; Ifosfamide; Immunoglobulins; Isophosphamide mustard; Oxaliplatin; Podophyllotoxin; Rituximab; Vitamins

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 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

• 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; 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)

• 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. 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

• ARM D: Known paroxysmal nocturnal hemoglobinuria (PNH)