Clinical Trials

The first 6 patients to be treated with R-ICE or ICE will enroll into Arm C for the safety analysis. These patients will not be randomized and will all receive IV AA. Patients receiving other chemotherapy regimens may still be enrolled to Arm C while the safety analysis is being conducted. The study has completed the safety analysis and will proceed to complete 30 evaluable patients on Arm C. We will then evaluate the results and refine the plan for Arms A/B. This arm has only one regimen and has a placebo. We will evaluate the accrual rate and results from Arm C before opening Arms A/B.

Arm D is added with LS Amendment 5, see eligibility inclusion and exclusion criteria in Sections 3.3 and 3.4.

Arm E is added with LS Amendment 10, see Pre-Registration and Registration eligibility inclusion and exclusion criteria in Sections 3.5 - 3.8.

3.1       Arms A, B and C Inclusion Criteria-

3.11     Age ≥18 years

3.12     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 in Section 3.14.  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.

3.13     Measureable or assessable disease: Measureable disease is defined as measurable by CT (dedicated CT or the CT portion of a PET/CT) or MRI: To be considered measureable, 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 ≥1.5cm 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.

3.14     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 (RICE);

·         cisplatin, cytosine arabinoside, dexamethasone (DHAP) or RDHAP;

·         gemcitabine, dexamethasone, cisplatin (GDP) or RGDP;

·         gemcitabine and oxaliplatin (GemOx) or RGemOx;

·         Oxaliplatin, cytosine arabinoside, dexamethasone (OAD) or ROAD.

3.15     ECOG Performance Status (PS) 0, 1 or 2 (Appendix I).

3.16     The following laboratory values obtained ≤14 days prior to registration (except creatinine which needs to be obtained ≤ 7 days prior to registration):

·         Hemoglobin ≥8.0 g/dL (may transfuse to meet this requirement)

·         Absolute neutrophil count (ANC) ≥1500/mm³

·         Platelet count ≥75000/mm³

·         Total bilirubin ≤ 2 x ULN (if >2 x ULN direct bilirubin is required and should be ≤ 1.5 x ULN)

·         Alanine aminotransferase (ALT) and Aspartate transaminase (AST) £3 x ULN (≤5 x ULN for patients with liver involvement)

·         Creatinine ≤1.6 mg/dL. If over 1.6 then the Calculated creatinine clearance must be ≥55 ml/min using the Cockcroft-Gault formula below:

3.17     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.

3.18     HIV test done ≤ 14 days prior to registration

·         If positive, the CD4 count must be >400.

3.19a   Provide written informed consent.

3.19b   Willingness to have a central venous line (PICC or PORT)    

3.19c   Willingness to provide mandatory blood specimens for correlative research (see Section 14.0).

3.19d   Willingness to provide mandatory tissue specimens for correlative research (see Section 17.0).

3.19e   Willingness to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study).

3.19f    Willingness to follow the requirements of the intravenous ascorbic acid program schedule.

3.2       Arms A, B, and C Exclusion Criteria

3.21     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

3.22     Any therapy ≤2weeks prior to registration.

EXCEPTIONS: 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. Patients can have monoclonal antibodies with steroids prior to registration. Exception: Palliative radiation is allowed.

3.23     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.            

3.24     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.

3.25     Receiving any other investigational agent which would be considered as a treatment for the lymphoma.

3.26     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.

3.27     History of myocardial infarction ≤6 months, or current symptomatic congestive heart failure or LVEF <40% or with > grade 2 diastolic dysfunction, with no symptoms or signs of heart failure.

3.28     Known G6PD (glucose-6-phosphate dehydrogenase) deficiency (below lower limit of normal).

3.29a   Patients with active CNS lymphoma or active CSF involvement with malignant cells requiring CNS-specific therapy with IV or IT MTX. Note: Patients with any prior CNS lymphoma (parenchymalor leptomeningeal) MUST be in CR in those compartments without any maintenance therapy required.

3.29b   Patients with uncontrolled or symptomatic kidney stones.

3.29c   Known paroxysmal nocturnal hemoglobinuria (PNH).

3.3       Arm D Inclusion Criteria

3.31     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)

3.32     ECOG Performance Status (PS) 0, 1 or 2

3.33     Patients must meet at least 1 of these 3 laboratory criteria to be enrolled and the values must be obtained ≤7 days prior to registration:

•          Hemoglobin ≤10g/dL

•          Absolute neutrophil count (ANC) ≤1000/mm3

•          Platelet count ≤100,000/mm3

3.34     The following laboratory values must be obtained ≤7 days prior to registration:

•          Total bilirubin ≤ 2 x ULN (if >2 x ULN direct bilirubin is required and should be ≤ 1.5 x ULN)

•          Alanine aminotransferase (ALT) and Aspartate transaminase (AST) ≤3 x ULN (≤5 x ULN for patients with liver involvement) Creatinine ≤1.6 mg/dL. If > 1.6, then the Calculated creatinine clearance must be ≥55 ml/min using the Cockcroft-Gault formula below:

•          Negative pregnancy test, 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.

3.35     Provide written informed consent.

3.36     Willingness to have a central venous line (PICC or PORT)   

3.37     Willingness to provide mandatory blood specimens for correlative research (see Section 14.0).

3.38     Willingness to return to enrolling institution (MCR) for follow-up (during the Active Monitoring Phase of the study).

3.39     Willingness to follow the requirements of the intravenous ascorbic acid program schedule.

3.4       Arm D Exclusion Criteria:

3.41     Bona-fide hematological neoplasm

3.42     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

3.43     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.

3.44     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.

3.45     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.

3.46     Patients with uncontrolled or symptomatic kidney stones.

3.47     Known paroxysmal nocturnal hemoglobinuria (PNH)

3.48     Known G6PD (glucose-6-phosphate dehydrogenase) deficiency (below lower limit of normal).

3.5       Arm E Pre-Registration – Inclusion Criteria

3.51     Age ≥ 18 years

3.52     New or an established diagnosis of 2016 WHO defined chronic myelomonocytic leukemia with a somatic TET2, IDH1, or IDH2 mutation  requiring treatment with DNA methyltransferase inhibitors/hypomethylating agents.

3.53     No prior CMML directed therapy.

·         Exception: Received ≤ 1 cycle of azacitidine, decitabine, erythropoiesis stimulating agent therapy (ESA), or oral decitabine and cedazuridine.

NOTE: Prior exposure to hydroxyurea is allowed.  Continuation beyond the first cycle must be discussed with the PI.

3.54     Willingness to provide mandatory research bone marrow sample for correlative research (See Section 14.0)

3.55     ECOG Performance Status (PS) 0, 1, or 2

3.56     Provide written informed consent.

3.57     The following laboratory vales obtained  ≤ 14 days prior to pre-registration:

·         Platelet count ³ 20,000/mm³

·         Total bilirubin ≤ 1.5 x ULN (≤ 3 x ULN for patients with Gilbert’s syndrome)

·         Alanine aminotransferase (ALT) and aspartate transaminase (AST) ≤ 3 x     ULN

3.58     Creatinine ≤ 1.6 mg/dL. If > 1.6, then the Calculated creatinine clearance must be ≥55 ml/min using the Cockcroft-Gault formula below:

3.59a     For a person of child-bearing potential (WOCBP): Must agree to use contraception or  take measures to avoid pregnancy during the study. Adequate contraception is defined as follows:

·         Complete true abstinence.

·         Consistent and correct use of one of the following methods of birth control:

o   Male partner who is sterile prior to the female patient’s entry into the study and is the sole sexual partner for that female patient.

o   Implants of levonorgestrel.

o   Injectable progestogen.

o   Intrauterine device (IUD) with a documented failure rate of less than 1% per year.

o   Oral contraceptive pill (either combined or progesterone only).

Barrier method, for example: diaphragm with spermicide or condom with spermicide in combination with either implants of levonorgestrel or injectable progestogen

3.59b   WOCBP must have a negative serum or urine pregnancy test ≤ 14 days prior to pre-registration. WOCBP will repeat the serum or urine pregnancy test ≤ 7 days prior to the initiation of starting treatment for confirmation of a negative pregnancy.

NOTE: WOCBP include any person who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea >12 consecutive months); or women on hormone replacement therapy with documented serum follicle stimulating hormone (FSH) level >35 mIU/mL. Even women who are using oral, implanted, or injectable contraceptive hormones or mechanical products such as an IUD or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy or practicing abstinence or where partner is sterile (e.g., vasectomy), must be considered to be of child-bearing potential.

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

3.59c   Persons who are able to father a child must use contraception during the study and for 3 months after the last treatment dose.

·         Complete true abstinence.

·         Latex condom with a spermicidal agent

·         Diaphragm with spermicide

3.6       Arm E Pre-Registration – Exclusion Criteria

3.61     MDS/MPN overlap syndromes other than CMML.

3.62     Active central nervous system disease.

3.63     Any active disease condition that would render the protocol treatment dangerous or impair the ability of the patient to receive study drug.

3.64     Concurrent active malignancy, except adequately treated nonmelanoma skin cancer. History of curatively treated in situ cancer of the cervix, curatively treated in situ cancer of the breast, or other solid tumors curatively treated is allowed as long as there is no evidence of disease for > 2 years.

3.65     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.

3.66     Disease requiring systemic treatment with systemic immunosuppression with steroid steroids at a dose of ≥ 20 mg/day prednisone (or equivalent). Exceptions: Intermittent use of bronchodilators or inhaled steroids, local steroid injections, topical steroids

3.67     Patients with uncontrolled or symptomatic kidney stones.

3.7       Arm E Registration – Inclusion Criteria

3.71     Willingness to provide mandatory blood specimens for correlative research (see Section 14.0).

3.72     Willingness to return to enrolling institution (MCR) for follow-up (during the Active Monitoring Phase of the study).

3.73     Recovered to Grade 1 or baseline or established as sequelae from all toxic effects of previous therapy except alopecia.

 3.74      Ability to complete questionnaire by themselves or with assistance.

3.75     Willingness to have a central venous line (PICC or PORT).

3.76     Willingness to follow the requirements of the intravenous ascorbic acid program schedule.

3.8       Arm E Registration – Exclusion Criteria

3.81     New York Heart Association (NYHA) class III/IV heart failure or active angina/angina equivalents (Appendix IV)

3.82     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.

3.83     Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, clinically significant cardiac arrhythmia, unstable angina pectoris, clinically significant nonhealing or healing wounds, pulmonary congestion or pulmonary edema, significant pulmonary disease (shortness of breath at rest or mild exertion), uncontrolled infection, clinical dehydration, or psychiatric illness/social situations that would limit compliance with study requirements.

3.84     Known G6PD (glucose-6-phosphate dehydrogenase) deficiency (below lower limit of normal).

3.85     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

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 08/10/2026. Questions regarding updates should be directed to the study team contact.