Oral Hepatitis C Treatment for Indolent Lymphoma (OPTImaL) Study

NCT02717949 | Terminated Phase 4 Results DMC

• 1 other identifier: 042015-086
• Study Type: interventional
• Target: 1
• Locations: 1 country
• Sites: 3

Brief Summary

There still remains the question if hepatitis C eradication with all oral therapy will lead to a regression or cure of the low grade lymphoma. Thus, the hypothesis of this study is that oral HCV therapy will lead to a high rate of hepatitis C eradication which will correlate with a reduction of the size and extent of low-grade lymphoma. The hypothesis of this study is that subjects with hepatitis C,regardless of genotype, who have low grade lymphoma, when treated for hepatitis C without pegylated interferon will have a regression of low grade non-Hodgkin's lymphoma. In this pilot study we will evaluate the effect of Sofosbuvir/ledipasvir or sofosbuvir/ribavirin based antiviral therapy on the course of a subset of HCV-related low grade B cell non-Hodgkin's lymphoma Primary Objective This study will assess the safety, as measured by adverse events, in subjects receiving hepatitis C treatment. Secondary Objective The secondary objective of this study is to assess the rate of overall response of B cell non-Hodgkin's lymphoma defined as either as partial response or complete response according to revised international working group criteria for non-Hodgkin lymphoma. Primary Endpoint Safety and tolerability of sofosbuvir/ledipasvir or sofosbuvir/ribavirin in subjects with B-cell non-Hodgkin's lymphoma will be assessed by number of adverse events and serious adverse events. In addition, the study will assess the number of subjects who had to stop treatment due to adverse events or serious adverse events. The study will also examine the number of subjects in which treatment for lymphoma had to be given due to clinical progression. Secondary Endpoints The secondary endpoint(s) of this study is to (1) Assess the rate of overall response of B-cell Non-Hodgkin's lymphoma defined as either as partial response or complete response according to revised international working group criteria for non-Hodgkin lymphoma. (2) Determine the rate of sustained viral response in subjects with low-grade lymphoma.

Conditions

Liver Disease

Keywords

hepatitis C; low-grade lymphoma

Outcome Measures

Primary Outcomes (1)

• Number Subjects Who Experience Adverse Events on HCV Treatment as Assessed by Division of AIDS (DAIDS) Adverse Event (AE) Grading Table Version 2.0.

  number of subjects who experience treatment-related adverse event on HCV treatment as assessed by DAIDS AE Grading Table version 2.

  from drug dispensation until post-treatment week 36

Secondary Outcomes (1)

• Number of Subjects Who Have a Change in Lymph Node Size From Baseline After HCV Treatment

  from baseline to post-treament week 36

Study Arms (2)

sofosbuvir/ledipasvir

EXPERIMENTAL

sofosbuvir and ledipasvir fixed dose combination given orally once a day for genotype 1 and 4.

Drug: sofosbuvir/ledipasvir

sofosbuvir and ribavirin

EXPERIMENTAL

Sofosbuvir 400 mg given orally once a day with weight-base ribavirin of 1200 mg for those \>75 kg and 1000 mg for those \<75kg given in divided dose twice a day. This intervention is for genotype 2 and 3

Drug: sofosbuvir; Drug: Ribavirin

Interventions

sofosbuvir/ledipasvir DRUG

sofosbuvir ledipasvir fixed dose combination given once a day by mouth

Also known as: Harvoni

sofosbuvir/ledipasvir

sofosbuvir DRUG

sofosbuvir 400 mg given one a daily orally and weight-based ribavirin given twice a day orally

Also known as: sovaldi

sofosbuvir and ribavirin

Ribavirin DRUG

ribavirin 1200 mg given orally in divided dose for those \>75kg and 1000 mg in divided dose for those \<75 kg.

Also known as: copegus, rebetol, ribasphere

sofosbuvir and ribavirin

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Willing and able to provide written informed consent.
• Male or female \>18 years of age
• Serum HCV RNA levels of \>1,000 IU per milliliter or higher
• HCV treatment experienced or naïve.
• HCV treatment naïve: No prior exposure to any Interferon, ribavirin, or other approved or experimental HCV-specific directly acting antivirals
• HCV Treatment-Experienced: Virologic failure after treatment with Pegylated interferon + ribavirin, Non-structural 3/4a (NS3/4A) protease inhibitor plus pegylated interferon + ribavirin, or regimen of sofosbuvir±ribavirin± pegylated interferon regimen.
• Chronic Hepatitis C based on the judgment of the investigator
• HCV genotype 1, 2, 3, 4
• If the patient is determined to be cirrhotic (based on criteria outlined earlier), the patient must have an ultrasound done within 6 months prior to enrollment with no evidence of hepatocellular carcinoma.
• Indolent Non-Hodgkin's lymphoma , which may include the following :
• Nodal Marginal zone lymphoma
• Extranodal marginal zone lymphoma (MALT)
• Splenic marginal zone lymphoma
• Follicular lymphoma Grade 1-3a with low tumor burden\*, FLIPI 2 risk category of either low (i.e. no risk factors) or intermediate (1-2 risk factors), and with no B symptoms. B symptoms are defined as:
• Fever (i.e., temperature \>38°C \[\>100.4°F\]) for 3 consecutive days

You may not qualify if:

• Life expectancy \< 6 months
• Any HCV treatment which uses pegylated interferon
• HCV genotype 3 Treatment experienced with cirrhosis
• Co-infection with hepatitis B
• Prior chemotherapy for lymphoma
• Lymphomas of other histologies other than the ones listed in section 3.3 above
• Follicular lymphoma with large cell transformation
• Decompensated liver disease in which pegylated interferon is contraindicated.
• Female who is pregnant or breast feeding and HCV treatment requires use of ribavirin.
• Solid organ transplant
• Any interferon- containing agent within 8 weeks prior to screening or any prior exposure to HCV-specific antivirals agent(s), other than NS3/ 4A protease inhibitor and sofosbuvir
• Known hypersensitivity to ledipasvir, sofosbuvir, or formulation excipients.
• On a prohibited medication which cannot be stopped during the duration of HCV treatment.
• Female subject who is pregnant or breastfeeding
• HIV-infection

Sponsors & Collaborators

• University of Texas Southwestern Medical Center: lead
• Memorial Sloan Kettering Cancer Center: collaborator
• Weill Medical College of Cornell University: collaborator

Study Sites (3)

Cornell Medical Center

New York, New York, 10065, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

UT Southwestern Medical Center

Dallas, Texas, 75390, United States

Location

Related Publications (12)

• Forghieri F, Luppi M, Barozzi P, Maffei R, Potenza L, Narni F, Marasca R. Pathogenetic mechanisms of hepatitis C virus-induced B-cell lymphomagenesis. Clin Dev Immunol. 2012;2012:807351. doi: 10.1155/2012/807351. Epub 2012 Jul 11.

  PMID: 22844326 BACKGROUND

• Peveling-Oberhag J, Arcaini L, Hansmann ML, Zeuzem S. Hepatitis C-associated B-cell non-Hodgkin lymphomas. Epidemiology, molecular signature and clinical management. J Hepatol. 2013 Jul;59(1):169-77. doi: 10.1016/j.jhep.2013.03.018. Epub 2013 Mar 27.

  PMID: 23542089 BACKGROUND

• Arcaini L, Merli M, Volpetti S, Rattotti S, Gotti M, Zaja F. Indolent B-cell lymphomas associated with HCV infection: clinical and virological features and role of antiviral therapy. Clin Dev Immunol. 2012;2012:638185. doi: 10.1155/2012/638185. Epub 2012 Aug 26.

  PMID: 22956970 BACKGROUND

• Kasama Y, Mizukami T, Kusunoki H, Peveling-Oberhag J, Nishito Y, Ozawa M, Kohara M, Mizuochi T, Tsukiyama-Kohara K. B-cell-intrinsic hepatitis C virus expression leads to B-cell-lymphomagenesis and induction of NF-kappaB signalling. PLoS One. 2014 Mar 20;9(3):e91373. doi: 10.1371/journal.pone.0091373. eCollection 2014.

  PMID: 24651473 BACKGROUND

• Hermine O, Lefrere F, Bronowicki JP, Mariette X, Jondeau K, Eclache-Saudreau V, Delmas B, Valensi F, Cacoub P, Brechot C, Varet B, Troussard X. Regression of splenic lymphoma with villous lymphocytes after treatment of hepatitis C virus infection. N Engl J Med. 2002 Jul 11;347(2):89-94. doi: 10.1056/NEJMoa013376.

  PMID: 12110736 BACKGROUND

• Vallisa D, Bernuzzi P, Arcaini L, Sacchi S, Callea V, Marasca R, Lazzaro A, Trabacchi E, Anselmi E, Arcari AL, Moroni C, Berte R, Lazzarino M, Cavanna L. Role of anti-hepatitis C virus (HCV) treatment in HCV-related, low-grade, B-cell, non-Hodgkin's lymphoma: a multicenter Italian experience. J Clin Oncol. 2005 Jan 20;23(3):468-73. doi: 10.1200/JCO.2005.06.008.

  PMID: 15659492 BACKGROUND

• Arcaini L, Vallisa D, Rattotti S, Ferretti VV, Ferreri AJM, Bernuzzi P, Merli M, Varettoni M, Chiappella A, Ambrosetti A, Tucci A, Rusconi C, Visco C, Spina M, Cabras G, Luminari S, Tucci M, Musto P, Ladetto M, Merli F, Stelitano C, d'Arco A, Rigacci L, Levis A, Rossi D, Spedini P, Mancuso S, Marino D, Bruno R, Baldini L, Pulsoni A. Antiviral treatment in patients with indolent B-cell lymphomas associated with HCV infection: a study of the Fondazione Italiana Linfomi. Ann Oncol. 2014 Jul;25(7):1404-1410. doi: 10.1093/annonc/mdu166. Epub 2014 May 5.

  PMID: 24799461 BACKGROUND

• Afdhal N, Zeuzem S, Kwo P, Chojkier M, Gitlin N, Puoti M, Romero-Gomez M, Zarski JP, Agarwal K, Buggisch P, Foster GR, Brau N, Buti M, Jacobson IM, Subramanian GM, Ding X, Mo H, Yang JC, Pang PS, Symonds WT, McHutchison JG, Muir AJ, Mangia A, Marcellin P; ION-1 Investigators. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med. 2014 May 15;370(20):1889-98. doi: 10.1056/NEJMoa1402454. Epub 2014 Apr 11.

  PMID: 24725239 BACKGROUND

• Gane EJ, Stedman CA, Hyland RH, Ding X, Svarovskaia E, Symonds WT, Hindes RG, Berrey MM. Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J Med. 2013 Jan 3;368(1):34-44. doi: 10.1056/NEJMoa1208953.

  PMID: 23281974 BACKGROUND

• Kowdley KV, Gordon SC, Reddy KR, Rossaro L, Bernstein DE, Lawitz E, Shiffman ML, Schiff E, Ghalib R, Ryan M, Rustgi V, Chojkier M, Herring R, Di Bisceglie AM, Pockros PJ, Subramanian GM, An D, Svarovskaia E, Hyland RH, Pang PS, Symonds WT, McHutchison JG, Muir AJ, Pound D, Fried MW; ION-3 Investigators. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med. 2014 May 15;370(20):1879-88. doi: 10.1056/NEJMoa1402355. Epub 2014 Apr 10.

  PMID: 24720702 BACKGROUND

• Lawitz E, Poordad FF, Pang PS, Hyland RH, Ding X, Mo H, Symonds WT, McHutchison JG, Membreno FE. Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin in treatment-naive and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): an open-label, randomised, phase 2 trial. Lancet. 2014 Feb 8;383(9916):515-23. doi: 10.1016/S0140-6736(13)62121-2. Epub 2013 Nov 5.

  PMID: 24209977 BACKGROUND

• Zeuzem S, Dusheiko GM, Salupere R, Mangia A, Flisiak R, Hyland RH, Illeperuma A, Svarovskaia E, Brainard DM, Symonds WT, Subramanian GM, McHutchison JG, Weiland O, Reesink HW, Ferenci P, Hezode C, Esteban R; VALENCE Investigators. Sofosbuvir and ribavirin in HCV genotypes 2 and 3. N Engl J Med. 2014 May 22;370(21):1993-2001. doi: 10.1056/NEJMoa1316145. Epub 2014 May 4.

  PMID: 24795201 BACKGROUND

MeSH Terms

Conditions

Liver Diseases; Hepatitis C; Lymphoma, Non-Hodgkin

Interventions

ledipasvir, sofosbuvir drug combination; Sofosbuvir; Ribavirin

Condition Hierarchy (Ancestors)

Digestive System Diseases; Blood-Borne Infections; Communicable Diseases; Infections; Hepatitis, Viral, Human; Virus Diseases; Flaviviridae Infections; RNA Virus Infections; Hepatitis; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Uridine Monophosphate; Uracil Nucleotides; Pyrimidine Nucleotides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleotides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleotides; Ribonucleosides; Nucleosides

Results Point of Contact

• Title: Mamta K.Jain, MD
• Organization: UT Southwestern Medical Center

mamta.jain@utsouthwestern.edu

214-648-9914

Study Officials

• Mamta K. Jain, MD

  University of Texas Southwestern Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 10, 2015
• First Posted: March 24, 2016
• Study Start: February 25, 2016
• Primary Completion: June 5, 2017
• Study Completion: July 18, 2017
• Last Updated: January 8, 2019
• Results First Posted: January 8, 2019

Record last verified: 2019-01

Locations

US (3)