Clinical Trial: NCT03418038 - My Cancer Genome

NCT03418038

Description:

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.

Related Conditions:

Diffuse Large B-Cell Lymphoma
Lymphoma

Recruiting Status:

Recruiting

Phase:

Phase 2

URL:

https://clinicaltrials.gov/show/NCT03418038

Trial Eligibility

Document

Title

Brief Title: Ascorbic Acid and Combination Chemotherapy for the Treatment of Relapsed or Refractory Lymphoma or Clonal Cytopenia of Undetermined Significance
Official Title: Phase 2 Trial of High Dose Intravenous Ascorbic Acid as an Adjunct to Salvage Chemotherapy in Relapsed / Refractory Lymphoma and Patients With Clonal Cytopenia of Undetermined Significance

Clinical Trial IDs

ORG STUDY ID: LS1781
SECONDARY ID: NCI-2018-00057
SECONDARY ID: LS1781
SECONDARY ID: P30CA015083
NCT ID: NCT03418038

Conditions

Clonal Cytopenia of Undetermined Significance
High Grade B-Cell Lymphoma With MYC and BCL2 or BCL6 Rearrangements
Recurrent Diffuse Large B-Cell Lymphoma
Recurrent Hodgkin Lymphoma
Recurrent Lymphoma
Refractory Diffuse Large B-Cell Lymphoma
Refractory Lymphoma

Interventions

Drug	Synonyms	Arms
Carboplatin	Blastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carboplatinum, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, JM-8, Nealorin, Novoplatinum, Paraplatin, Paraplatin AQ, Paraplatine, Platinwas, Ribocarbo	Arm A (ascorbic acid, combination chemotherapy)
Cisplatin	Abiplatin, Blastolem, Briplatin, CDDP, Cis-diammine-dichloroplatinum, Cis-diamminedichloridoplatinum, Cis-diamminedichloro Platinum (II), Cis-diamminedichloroplatinum, Cis-dichloroammine Platinum (II), Cis-platinous Diamine Dichloride, Cis-platinum, Cis-platinum II, Cis-platinum II Diamine Dichloride, Cismaplat, Cisplatina, Cisplatinum, Cisplatyl, Citoplatino, Citosin, Cysplatyna, DDP, Lederplatin, Metaplatin, Neoplatin, Peyrone''s Chloride, Peyrone''s Salt, Placis, Plastistil, Platamine, Platiblastin, Platiblastin-S, Platinex, Platinol, Platinol- AQ, Platinol-AQ, Platinol-AQ VHA Plus, Platinoxan, Platinum, Platinum Diamminodichloride, Platiran, Platistin, Platosin	Arm A (ascorbic acid, combination chemotherapy)
Cytarabine	.beta.-Cytosine arabinoside, 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-.beta.-D-Arabinofuranosylcytosine, 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-Beta-D-arabinofuranosylcytosine, 1.beta.-D-Arabinofuranosylcytosine, 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-, 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-, Alexan, Ara-C, ARA-cell, Arabine, Arabinofuranosylcytosine, Arabinosylcytosine, Aracytidine, Aracytin, Aracytine, Beta-Cytosine Arabinoside, CHX-3311, Cytarabinum, Cytarbel, Cytosar, Cytosine Arabinoside, Cytosine-.beta.-arabinoside, Cytosine-beta-arabinoside, Erpalfa, Starasid, Tarabine PFS, U 19920, U-19920, Udicil, WR-28453	Arm A (ascorbic acid, combination chemotherapy)
Dexamethasone	Aacidexam, Adexone, Aknichthol Dexa, Alba-Dex, Alin, Alin Depot, Alin Oftalmico, Amplidermis, Anemul mono, Auricularum, Auxiloson, Baycadron, Baycuten, Baycuten N, Cortidexason, Cortisumman, Decacort, Decadrol, Decadron, Decadron DP, Decalix, Decameth, Decasone R.p., Dectancyl, Dekacort, Deltafluorene, Deronil, Desamethasone, Desameton, Dexa-Mamallet, Dexa-Rhinosan, Dexa-Scheroson, Dexa-sine, Dexacortal, Dexacortin, Dexafarma, Dexafluorene, Dexalocal, Dexamecortin, Dexameth, Dexamethasone Intensol, Dexamethasonum, Dexamonozon, Dexapos, Dexinoral, Dexone, Dinormon, Dxevo, Fluorodelta, Fortecortin, Gammacorten, Hemady, Hexadecadrol, Hexadrol, Lokalison-F, Loverine, Methylfluorprednisolone, Millicorten, Mymethasone, Orgadrone, Spersadex, TaperDex, Visumetazone, ZoDex	Arm A (ascorbic acid, combination chemotherapy)
Etoposide	Demethyl Epipodophyllotoxin Ethylidine Glucoside, EPEG, Lastet, Toposar, Vepesid, VP 16, VP 16-213, VP-16, VP-16-213, VP16	Arm A (ascorbic acid, combination chemotherapy)
Gemcitabine Hydrochloride	dFdCyd, Difluorodeoxycytidine Hydrochloride, FF 10832, FF-10832, FF10832, Gemcitabine HCI, Gemzar, LY-188011, LY188011	Arm C (ascorbic acid and combination chemotherapy)
Ifosfamide	Asta Z 4942, Asta Z-4942, Cyfos, Holoxan, Holoxane, Ifex, IFO, IFO-Cell, Ifolem, Ifomida, Ifomide, Ifosfamidum, Ifoxan, IFX, Iphosphamid, Iphosphamide, Iso-Endoxan, Isoendoxan, Isophosphamide, Mitoxana, MJF 9325, MJF-9325, Naxamide, Seromida, Tronoxal, Z 4942, Z-4942	Arm A (ascorbic acid, combination chemotherapy)
Oxaliplatin	1-OHP, Ai Heng, Aiheng, Dacotin, Dacplat, Diaminocyclohexane Oxalatoplatinum, Eloxatin, Eloxatine, JM-83, Oxalatoplatin, Oxalatoplatinum, RP 54780, RP-54780, SR-96669	Arm C (ascorbic acid and combination chemotherapy)
Rituximab	ABP 798, BI 695500, C2B8 Monoclonal Antibody, Chimeric Anti-CD20 Antibody, CT-P10, IDEC-102, IDEC-C2B8, IDEC-C2B8 Monoclonal Antibody, MabThera, Monoclonal Antibody IDEC-C2B8, PF-05280586, Rituxan, Rituximab ABBS, Rituximab Biosimilar ABP 798, Rituximab Biosimilar BI 695500, Rituximab Biosimilar CT-P10, Rituximab Biosimilar GB241, Rituximab Biosimilar IBI301, Rituximab Biosimilar JHL1101, Rituximab Biosimilar PF-05280586, Rituximab Biosimilar RTXM83, Rituximab Biosimilar SAIT101, Rituximab Biosimilar SIBP-02, rituximab biosimilar TQB2303, rituximab-abbs, RTXM83, Truxima	Arm A (ascorbic acid, combination chemotherapy)

Purpose

Detailed 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) 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 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.

Trial Arms

Name	Type	Description	Interventions
Arm A (ascorbic acid, combination chemotherapy)	Experimental	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 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.	Carboplatin Cisplatin Cytarabine Dexamethasone Etoposide Ifosfamide Rituximab
Arm B (placebo, combination chemotherapy)	Active Comparator	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.	Carboplatin Cisplatin Cytarabine Dexamethasone Etoposide Ifosfamide Rituximab
Arm C (ascorbic acid and combination chemotherapy)	Experimental	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.	Carboplatin Cisplatin Cytarabine Dexamethasone Etoposide Gemcitabine Hydrochloride Ifosfamide Oxaliplatin
Arm D (ascobic acid)	Experimental	Patients receive ascorbic acid IV TIW. Treatments repeat every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity.

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 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)

Maximum Eligible Age:	N/A
Minimum Eligible Age:	18 Years
Eligible Gender:	All
Healthy Volunteers:	No

Primary Outcome Measures

Measure:	Overall response rate (ORR) (Arms A and B)
Time Frame:	Up to 2 years
Safety Issue:
Description:	Defined as an objective status of complete response (CR) or partial response (PR) evaluated by Response Evaluation Criteria in Lymphoma (RECIL) criteria after 2 courses of treatment in all arms. Will be compared between the two arms. The proportion of successes will be estimated in each arm by the number of successes divided by the total number of evaluable patients. Exact binomial ninety-five percent confidence intervals for the true success proportion will be calculated in each arm. For the diffuse large B-cell lymphoma (DLBCL) arms, comparison of overall response rates between the two treatment groups will be performed using a one-sided chi-square test at significance level 0.10.

Secondary Outcome Measures

Measure:	Clinical benefit rate (Arms A, B, and C)
Time Frame:	Up to 2 years
Safety Issue:
Description:	Will be estimated in each arm by the number of patients who achieve a CR, PR, minor response (MR), or stable disease (SD) on the cycle 2 response assessment divided by the total number of evaluable patients. Exact binomial 95% confidence intervals for the true success rate will be calculated. The clinical benefit rate will be compared between the DLBCL arms using the chi-square test (or Fisher's exact test if the data in the contingency table is sparse).

Measure:	Overall survival
Time Frame:	From registration to death due to any cause, assessed up to 2 years
Safety Issue:
Description:	The distribution of overall survival will be estimated in each arm using the method of Kaplan-Meier. In the DLBCL arms, the comparison of overall survival between the two treatment arms will be based on the log-rank test.

Measure:	Progression-free survival
Time Frame:	From date of first treatment to the earliest date of documentation of disease progression or death due to any cause, assessed up to 2 years
Safety Issue:
Description:	The distribution of progression-free survival will be estimated in each arm using the method of Kaplan-Meier. In the DLBCL arms, the comparison of progression-free survival between the two treatment arms will be based on the log-rank test.

Measure:	Percent of transplant eligible patients proceeding to transplant (Arms A, B and C)
Time Frame:	Up to 2 years
Safety Issue:
Description:	Will be estimated in each arm by the number of patients proceeding to transplant divided by the total number of patients who were considered transplant eligible. Exact binomial 95% confidence intervals for the true success rate will be calculated. The rate will be compared between the DLBCL arms using the chi-square test (or Fisher's exact test if the data in the contingency table is sparse).

Measure:	Transfusion dependency (Arm D)
Time Frame:	Up to 2 years
Safety Issue:
Description:	Transfusion dependency will be summarized descriptively. The number of patients transfusion dependent at baseline and during follow-up will be summarized.

Measure:	Incidence of adverse events
Time Frame:	Up to 2 years
Safety Issue:
Description:	Assessed using Common Terminology Criteria for Adverse Events (CTCAE). The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration. In the DLBCL arms, the overall adverse event rates for Grade 3 or higher hematologic and non-hematologic adverse events at least possibly related to treatment will be compared between the two treatment groups using the chi-square test (or Fisher's exact test if the data in the contingency table is sparse). The rate of febrile neutropenia will be evaluated in each arm.

Measure:	Incidence of adverse events
Time Frame:	Up to 2 years
Safety Issue:
Description:	Assessed using Patient Reported Outcomes (PRO)-CTCAE (Arms A and B). PRO-CTCAE scores range from 0-4, with corresponding response choices for frequency (Never / Rarely / Occasionally / Frequently / Almost constantly), for severity (None / Mild / Moderate / Severe / Very severe) and interference (Not at all / A little bit / Somewhat / Quite a bit / Very much). The scores for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns. PRO-CTCAE scores will be compared between the two treatment groups using the chi-square test (or Fisher's exact test if the data in the contingency table is sparse).

Measure:	Continued salvage therapy beyond cycle 2 (Arm A, B and C)
Time Frame:	Up to 2 years
Safety Issue:
Description:	Will be assessed by evaluating the number of patients who achieve an improved response after cycle 4 compared to the cycle 2 assessment in patients who received additional cycles of ascorbic acid/placebo added to salvage therapy beyond cycle 2. In addition, the number of patients who changed salvage therapies after cycle 2 will be assessed. This analysis will be primarily descriptive.

Details

Phase:	Phase 2
Primary Purpose:	Interventional
Overall Status:	Recruiting
Lead Sponsor:	Mayo Clinic

Last Updated

August 26, 2021

Clinical Trials /

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