A Phase 1/2 interventional study of Cyclophosphamide and Doxorubicin Hydrochloride in Ann Arbor Stage II Non-Hodgkin Lymphoma, Ann Arbor Stage III Non-Hodgkin Lymphoma and Ann Arbor Stage IV Non-Hodgkin Lymphoma, sponsored by National Cancer Institute (NCI). Active, not recruiting at 190 sites in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2026-09-09.
Sponsored by National Cancer Institute (NCI) · Phase 1/2, Interventional, and Treatment
This phase I/II trial is studying the side effects and best dose of vorinostat when given together with rituximab and combination chemotherapy and to see how well it works in treating patients with newly diagnosed stage II, stage III, or stage IV diffuse large B-cell lymphoma. Vorinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the cancer. Monoclonal antibodies, such as rituximab, can block cancer cell growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cell-killing substances to them. Drugs used in chemotherapy, such as cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving vorinostat together with rituximab and combination chemotherapy may kill more cancer cells.
PRIMARY OBJECTIVES:
I. To find a safe dose of vorinostat to be used in combination with R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone) (vorinostat-R-CHOP). (Phase I) II. To estimate the 2-year progression-free survival (PFS) rate in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) treated with vorinostat and R-CHOP therapy (vorinostat-R-CHOP). (Phase II) III. To estimate the response rate (complete and partial) and 2-year overall survival rate. (Phase II) IV. To evaluate the toxicity of vorinostat-R-CHOP in patients with newly diagnosed DLBCL. (Phase II) V. To assess whether pre-treatment acetylation status of histones, expression of major histocompatibility complex (MHC) class II genes, and/or percentage of cluster of differentiation (CD)8+ tumor infiltrating lymphocytes correlate with progression-free survival. (Phase II) VI. To explore whether treatment with vorinostat-R-CHOP increases histone acetylation, alters expression of MHC class II proteins, or alters percentage of T-cell subsets (CD8+, CD4+, forkhead box P3 [FOXP3]+) or infiltrating macrophages. (Phase II) VII. To explore whether histone acetylation status of tumor tissues correlates with MHC class II expression of peripheral blood B cells and lymphocyte subsets. (Phase II) VIII. To explore whether the change in systemic levels of immune cytokines with vorinostat-R-CHOP correlates with lymphoma symptoms, response, progression-free or overall survival. (Phase II)
OUTLINE: This is a phase I, dose escalation study of vorinostat followed by a phase II study.
Patients receive vorinostat orally (PO) once daily on days 1-5 or 1-9 (according to dose level), rituximab intravenously (IV), cyclophosphamide IV over 30-60 minutes, doxorubicin hydrochloride IV, and vincristine sulfate IV on day 3. Patients also receive prednisone PO once daily on days 3-7. Treatment repeats every 21 days for 8 courses in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed every 6 months for 2 years, and then annually for 3 years.
National Cancer Institute (NCI) is the lead sponsor of 3,506 studies on the registry; 334 are open to participants now.
Of its 402 completed or terminated interventional studies of FDA-regulated products, 365 (91%) have results posted.
Counted across the registry records on this site, refreshed daily.
Inclusion Criteria:
Patients receive vorinostat PO once daily on days 1-5 or 1-9 (according to dose level), rituximab IV, cyclophosphamide IV over 30-60 minutes, doxorubicin hydrochloride IV, and vincristine sulfate IV on day 3. Patients also receive prednisone PO once daily on days 3-7. Treatment repeats every 21 days for 8 courses in the absence of disease progression or unacceptable toxicity.
Drug: Cyclophosphamide · Drug: Doxorubicin Hydrochloride · Other: Laboratory Biomarker Analysis · Drug: Prednisone · Biological: Rituximab · Drug: Vincristine Sulfate · Drug: Vorinostat
Given IV
Also known as: (-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Asta B 518, B 518, B-518, B518, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamide Monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Frindovyx, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR 138719, WR- 138719, WR-138719, WR138719
Given IV
Also known as: 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI), ADM, Adriacin, Adriamycin, Adriamycin Hydrochloride, Adriamycin PFS, Adriamycin RDF, ADRIAMYCIN, HYDROCHLORIDE, Adriamycine, Adriblastina, Adriblastine, Adrimedac, Chloridrato de Doxorrubicina, DOX, DOXO-CELL, Doxolem, Doxorubicin HCl, Doxorubicin.HCl, Doxorubin, Farmiblastina, FI 106, FI-106, FI106, hydroxydaunorubicin, Rubex
Correlative studies
Given IV
Also known as: .delta.1-Cortisone, 1, 2-Dehydrocortisone, Adasone, Cortancyl, Dacortin, DeCortin, Decortisyl, Decorton, Delta 1-Cortisone, Delta-Dome, Deltacortene, Deltacortisone, Deltadehydrocortisone, Deltasone, Deltison, Deltra, Econosone, Lisacort, Meprosona-F, Metacortandracin, Meticorten, Ofisolona, Orasone, Panafcort, Panasol-S, Paracort, Perrigo Prednisone, PRED, Predicor, Predicorten, Prednicen-M, Prednicort, Prednidib, Prednilonga, Predniment, Prednisone Intensol, Prednisonum, Prednitone, Promifen, Rayos, Servisone, SK-Prednisone
Given IV
Also known as: ABP 798, ABP-798, ABP798, BI 695500, BI-695500, BI695500, Blitzima, C2B8 Monoclonal Antibody, Chimeric Anti-CD20 Antibody, CT P10, CT-P10, CTP10, GP 2013, GP-2013, GP2013, IDEC 102, IDEC-102, IDEC-C2B8, IDEC-C2B8 Monoclonal Antibody, IDEC102, Ikgdar, Mabtas, MabThera, Monoclonal Antibody IDEC-C2B8, PF 05280586, PF-05280586, PF05280586, Riabni, Ritemvia, Rituxan, Rituximab ABBS, Rituximab ARRX, Rituximab Biosimilar ABP 798, Rituximab Biosimilar BI 695500, Rituximab Biosimilar CT-P10, Rituximab Biosimilar GB241, Rituximab Biosimilar GP2013, Rituximab Biosimilar IBI301, Rituximab Biosimilar JHL1101, Rituximab Biosimilar PF-05280586, Rituximab Biosimilar RTXM83, Rituximab Biosimilar SAIT101, Rituximab Biosimilar SIBP-02, rituximab biosimilar TQB2303, Rituximab PVVR, Rituximab-abbs, Rituximab-arrx, Rituximab-blit, Rituximab-pvvr, Rituximab-rite, Rituximab-rixa, Rituximab-rixi, Rixathon, Riximyo, RTXM 83, RTXM-83, RTXM83, Ruxience, Truxima
Given IV
Also known as: Kyocristine, Leurocristine Sulfate, Leurocristine, sulfate, Oncovin, Vincasar, Vincosid, Vincrex, Vincristine, sulfate
Given PO
Also known as: L-001079038, MSK-390, SAHA, Suberanilohydroxamic Acid, Suberoylanilide Hydroxamic Acid, Zolinza
Safe Dose of Vorinostat to be Used in Combination With R-CHOP Assessed by CTCAE Version 4.0 (Phase I)
Safe dose of Vorinostat (in combination with R-CHOP) at which 3/10 or fewer patients have doselimiting toxicities (DLT). Toxicities graded according to the NCI Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE 4.0). DLT apply only during cycle 1 and should be drug-related (possible, probable, or definite).
Time frame: 21 days
Progression-free Survival (Phase II)
From date of registration to date of first documentation of progressive disease, or death due to any cause. Patients last known to be alive and progression free are censored at date of last contact.
Time frame: Up to 2 years
Overall Survival (Phase II)
From date of registration to date of death due to any cause. Patients last known to be alive are censored at date of last contact.
Time frame: Up to 2 years
Response Rate (Complete Response [CR]+Partial Response [PR]) (Phase II)
Objective disease status is evaluated according to the 2007 revised Cheson et al. criteria. Complete Response(CR) is a complete disappearance of all disease with the exception of nodes. No new lesions. previously enlarged organs must have regressed and not be palpable. Bone marrow (BM) must be negative if positive at baseline. Normalization of markers. Partial Response (PR) is a 50% decrease in the sum of products of greatest diameters (SPD) for up to 6 identified dominant lesions, including spleenic and hepatic nodules from baseline. No new lesions and no increase in the size of liver, spleen or other nodes.
Time frame: Up to week 26
Toxicity of Vorinostat-R-CHOP in Patients With Newly Diagnosed DLBCL
Incidence of toxicity as assessed by the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. For each patient, worst grade of each event type is reported. Grade 3 = Severe, Grade 4 = Life-threatening, Grade 5 = Fatal.
Time frame: Up to week 26
| Milestone | Ph I: R-CHOP+Vorinostat (400mg D1-9) | Ph II: R-CHOP+Vorinostat |
|---|---|---|
| Started | 11 | 72 |
| Eligible and began protocol therapy | 9 | 63 |
| Completed | 4 | 34 |
| Not completed | 7 | 38 |
| Withdrew: Adverse event | 3 | 16 |
| Withdrew: Withdrawal by subject | 1 | 8 |
| Withdrew: Progression/relapse | 0 | 2 |
| Withdrew: Death | 0 | 2 |
| Withdrew: Not protocol specified | 1 | 1 |
| Withdrew: Ineligible | 1 | 7 |
| Withdrew: Not start protocol treatment | 1 | 2 |
Safe dose of Vorinostat (in combination with R-CHOP) at which 3/10 or fewer patients have doselimiting toxicities (DLT). Toxicities graded according to the NCI Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE 4.0). DLT apply only during cycle 1 and should be drug-related (possible, probable, or definite).
| mg PO Once daily Days 1-9 | Ph I: R-CHOP+Vorinostat (400mg D1-9) |
|---|---|
| Safe Dose of Vorinostat to be Used in Combination With R-CHOP Assessed by CTCAE Version 4.0 (Phase I) | 400 |
From date of registration to date of first documentation of progressive disease, or death due to any cause. Patients last known to be alive and progression free are censored at date of last contact.
| percentage of participants | Ph II: R-CHOP+Vorinostat |
|---|---|
| Progression-free Survival (Phase II) | 73 (59.6 to 81.9) |
From date of registration to date of death due to any cause. Patients last known to be alive are censored at date of last contact.
| percentage of participants | Ph II: R-CHOP+Vorinostat |
|---|---|
| Overall Survival (Phase II) | 86 (74.3 to 92.3) |
Objective disease status is evaluated according to the 2007 revised Cheson et al. criteria. Complete Response(CR) is a complete disappearance of all disease with the exception of nodes. No new lesions. previously enlarged organs must have regressed and not be palpable. Bone marrow (BM) must be negative if positive at baseline. Normalization of markers. Partial Response (PR) is a 50% decrease in the sum of products of greatest diameters (SPD) for up to 6 identified dominant lesions, including spleenic and hepatic nodules from baseline. No new lesions and no increase in the size of liver, spleen or other nodes.
| percentage of participants | Ph II: R-CHOP+Vorinostat |
|---|---|
| Response Rate (Complete Response [CR]+Partial Response [PR]) (Phase II) | 81 (69.1 to 89.8) |
Incidence of toxicity as assessed by the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. For each patient, worst grade of each event type is reported. Grade 3 = Severe, Grade 4 = Life-threatening, Grade 5 = Fatal.
| Participants | Ph I: R-CHOP+Vorinostat (400mg D1-9) | Ph II: R-CHOP+Vorinostat |
|---|---|---|
| Abdominal pain | 1 | 3 |
| Acute kidney injury | 0 | 1 |
| Alanine aminotransferase increased | 0 | 1 |
| Anemia | 4 | 22 |
| Anorexia | 1 | 2 |
| Aspartate aminotransferase increased | 0 | 1 |
| Atrial fibrillation | 0 | 1 |
| Bladder spasm | 0 | 1 |
| Bronchial infection | 0 | 1 |
| CD4 lymphocytes decreased | 0 | 1 |
| CPK increased | 0 | 1 |
| Carbon monoxide diffusing capacity decreased | 0 | 1 |
| Colitis | 1 | 0 |
| Creatinine increased | 1 | 0 |
| Cystitis noninfective | 0 | 1 |
| Dehydration | 2 | 4 |
| Depression | 1 | 0 |
| Diarrhea | 2 | 2 |
| Disseminated intravascular coagulation | 1 | 0 |
| Dizziness | 1 | 0 |
| Duodenal perforation | 0 | 1 |
| Dysphagia | 0 | 1 |
| Dyspnea | 0 | 1 |
| Electrocardiogram QT corrected interval prolonged | 1 | 1 |
| Fatigue | 3 | 9 |
| Febrile neutropenia | 3 | 24 |
| Fecal incontinence | 0 | 1 |
| Gastrointestinal disorders - Other, specify | 0 | 1 |
| Generalized muscle weakness | 2 | 2 |
| Hematuria | 1 | 0 |
| Hiccups | 0 | 1 |
| Hyperglycemia | 0 | 4 |
| Hypoalbuminemia | 1 | 3 |
| Hypocalcemia | 1 | 0 |
| Hypokalemia | 2 | 8 |
| Hyponatremia | 0 | 6 |
| Hypophosphatemia | 1 | 2 |
| Hypotension | 0 | 3 |
| Infections and infestations - Other, specify | 1 | 3 |
| Jejunal perforation | 0 | 1 |
| Left ventricular systolic dysfunction | 0 | 1 |
| Leukocytosis | 0 | 1 |
| Lung infection | 0 | 4 |
| Lymphocyte count decreased | 4 | 20 |
| Mucosal infection | 0 | 1 |
| Mucositis oral | 1 | 3 |
| Multi-organ failure | 1 | 0 |
| Myalgia | 1 | 2 |
| Myocardial infarction | 0 | 2 |
| Nausea | 1 | 3 |
| Neutrophil count decreased | 8 | 37 |
| Obstruction gastric | 0 | 1 |
| Pain | 0 | 1 |
| Paronychia | 0 | 1 |
| Peripheral motor neuropathy | 1 | 0 |
| Platelet count decreased | 4 | 22 |
| Pneumonitis | 0 | 1 |
| Recurrent laryngeal nerve palsy | 0 | 1 |
| Respiratory failure | 0 | 1 |
| Sepsis | 3 | 11 |
| Sinus tachycardia | 0 | 1 |
| Sinusitis | 0 | 1 |
| Small intestinal obstruction | 0 | 1 |
| Stoma site infection | 0 | 1 |
| Syncope | 0 | 4 |
| Urinary tract infection | 0 | 3 |
| Urinary tract pain | 0 | 2 |
| Urine output decreased | 1 | 0 |
| Vasovagal reaction | 0 | 1 |
| Visceral arterial ischemia | 1 | 0 |
| Vomiting | 0 | 2 |
| Weight loss | 0 | 3 |
| White blood cell decreased | 7 | 32 |
Collected over Up to week 26. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Ph I: R-CHOP+Vorinostat (400mg D1-9) | — | 5/9 (55.6%) | 9/9 (100%) |
| Ph II: R-CHOP+Vorinostat | — | 44/63 (69.8%) | 63/63 (100%) |
| Event | Ph I: R-CHOP+Vorinostat (400mg D1-9) | Ph II: R-CHOP+Vorinostat |
|---|---|---|
| Platelet count decreasedInvestigations | 4/9 | 16/63 |
| Febrile neutropeniaBlood and lymphatic system disorders | 3/9 | 22/63 |
| AnemiaBlood and lymphatic system disorders | 3/9 | 13/63 |
| SepsisInfections and infestations | 3/9 | 8/63 |
| Neutrophil count decreasedInvestigations | 3/9 | 16/63 |
| White blood cell decreasedInvestigations | 2/9 | 10/63 |
| HypokalemiaMetabolism and nutrition disorders | 2/9 | 3/63 |
| Disseminated intravascular coagulationBlood and lymphatic system disorders | 1/9 | 0/63 |
| Abdominal painGastrointestinal disorders | 1/9 | 1/63 |
| ColitisGastrointestinal disorders | 1/9 | 0/63 |
| Event | Ph I: R-CHOP+Vorinostat (400mg D1-9) | Ph II: R-CHOP+Vorinostat |
|---|---|---|
| AnemiaBlood and lymphatic system disorders | 9/9 | 52/63 |
| NauseaGastrointestinal disorders | 8/9 | 43/63 |
| FatigueGeneral disorders | 8/9 | 45/63 |
| Platelet count decreasedInvestigations | 8/9 | 32/63 |
| White blood cell decreasedInvestigations | 8/9 | 40/63 |
| DiarrheaGastrointestinal disorders | 7/9 | 31/63 |
| Lymphocyte count decreasedInvestigations | 7/9 | 26/63 |
| Neutrophil count decreasedInvestigations | 7/9 | 35/63 |
| AlopeciaSkin and subcutaneous tissue disorders | 7/9 | 21/63 |
| AnorexiaMetabolism and nutrition disorders | 6/9 | 23/63 |
Eligible patients who began protocol therapy
| Age, Continuous(years) | Ph I: R-CHOP+Vorinostat (400mg D1-9) | Ph II: R-CHOP+Vorinostat | Total |
|---|---|---|---|
| Median | 66.9 (46.4 to 83.8) | 64.1 (19.6 to 80.8) | 64.2 (19.6 to 83.8) |
| Sex: Female, Male(Participants) | Ph I: R-CHOP+Vorinostat (400mg D1-9) | Ph II: R-CHOP+Vorinostat | Total |
|---|---|---|---|
| Female | 3 | 27 | 30 |
| Male | 6 | 36 | 42 |
| Race/Ethnicity, Customized(participants) | Ph I: R-CHOP+Vorinostat (400mg D1-9) | Ph II: R-CHOP+Vorinostat | Total |
|---|---|---|---|
| White | 9 | 54 | 63 |
| Black | 0 | 3 | 3 |
| Asian | 0 | 5 | 5 |
| Unknown | 0 | 1 | 1 |
| Race/Ethnicity, Customized(participants) | Ph I: R-CHOP+Vorinostat (400mg D1-9) | Ph II: R-CHOP+Vorinostat | Total |
|---|---|---|---|
| Hispanic | 3 | 4 | 7 |
| Non-Hispanic | 6 | 59 | 65 |
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