Oral Hepatitis C Treatment for Indolent Lymphoma (OPTImaL) Study

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.

Methods and Study Design

The study will plans to enroll approximately 21 subjects over the next 6-12 months for this study.

Subjects with low grade lymphoma with confirmed diagnosis of hepatitis C with a viral load \> 1000 will be included in this study. Subjects may be treatment naïve or experienced to hepatitis C therapy, however subjects must be treatment naïve to non-Hodgkin's lymphoma treatment to be included in this study. All subjects will undergo staging studies at the time of study screening which will include a whole body scans and a bone marrow biopsy. In those with a prior bone marrow biopsy, those who had bone marrow involvement and biopsy was \<3 months from screening, then an additional biopsy is not needed. If bone marrow biopsy did not show bone marrow involvement, a repeat bone marrow biopsy is needed at screening. If complete data is not available from a prior biopsy, a repeat bone marrow biopsy will need to be done. In addition, patients will have staging of liver disease by serologic markers of liver inflammation, such as aspartate aminotransferase (AST) to platelet ratio (APRI) and FibroTest® or (Fibro Sure®) or FibroScan®. If these methods are inconclusive, then a liver biopsy may be obtained to determine if the patient has cirrhosis. Patients will be treated regardless of stage of fibrosis. The rationale for examining cirrhosis is that these patients may not respond as well and will require further surveillance for hepatocellular cancer every 6 months. Additionally, hepatitis C viral load and genotype will be determined prior to initiation of hepatitis C treatment.

Setting:

This will be a multi- center study conducted at University of Texas Southwestern Medical Center, Cornell Medical Center, and Memorial Sloan Kettering Cancer Center. Each site would be expected to enroll 7 subjects in 6-12 months.

Treatment

Genotype 1:

Treatment Naïve, with or without cirrhosis: sofosbuvir/ledipasvir one pill once a day for 12 weeks.

Treatment experienced, with cirrhosis: sofosbuvir/ledipasvir one pill once a day with weight-based ribavirin for 12 weeks. Weight-based ribavirin refers to use 1200 mg of ribavirin in divided doses for those ≥75 kg and 1000 mg in divided dose for those \<75kg.

Treatment experienced with cirrhosis : sofosbuvir/ledipasvir one pill once a day for 24 weeks. This option is for subjects who are unable to take ribavirin.

Genotype 2:

Treatment naïve or experienced without cirrhosis: sofosbuvir 400mg once daily and ribavirin 1000/1200 mg weight-based dosing in divided dose twice a day for 12 weeks.Treatment naïve or experienced with cirrhosis: sofosbuvir 400 mg and weight-based ribavirin for 16 weeks

Genotype 3:

Treatment naïve, non-cirrhotic: sofosbuvir/ledipasvir fixed dose combination combined with weight-based ribavirin for 12 weeks or treatment naïve with cirrhosis: sofosbuvir 400 mg daily with weight-based ribavirin for 24 weeks.

Treatment experienced with cirrhosis will be excluded as the best treatment for this population would require pegylated interferon.

Genotype 4:

Treatment naïve with or without cirrhosis or treatment experienced without cirrhosis: sofosbuvir/Ledipasvir fixed dose combination for 12 weeks.

Treatment experienced with cirrhosis: sofosbuvir/ledipasvir for 24 weeks.

Eligibility Criteria:
Inclusion Criteria:

1. Willing and able to provide written informed consent.
2. Male or female \>18 years of age
3. Serum HCV RNA levels of \>1,000 IU per milliliter or higher
4. 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.
5. Chronic Hepatitis C based on the judgment of the investigator
6. HCV genotype 1, 2, 3, 4
7. 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.
8. 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
     * Weight loss exceeding 10% of body weight in 6 months
     * Drenching night sweats
   * Lymphoplasmacytic lymphoma
9. No prior chemotherapy

   * Low tumor burden is defined as normal lactate dehydrogenase, largest nodal or extranodal mass less than 7 cm, up to three nodal sites containing nodes with a diameter greater than 3 cm, no clinically significant serous effusions detectable by physical examination or positron emission tomography (PET)/CT scan, and spleen enlargement up to 16 cm by CT without any evidence of portal hypertension.
10. Karnofsky performance status \> 70%
11. Creatinine clearance ≥60 mL/min, as calculated by Cockcroft-Gault equation
12. If patient will need ribavirin in their regimen then the following inclusion:

    * Hg \>12 g/dL for male
    * Hg \>11 g/dL for female
13. All women of child-bearing potential who take ribavirin will need to have a negative urine pregnancy test.

Exclusion Criteria:

1. Life expectancy \< 6 months
2. Any HCV treatment which uses pegylated interferon
3. HCV genotype 3 Treatment experienced with cirrhosis
4. Co-infection with hepatitis B
5. Prior chemotherapy for lymphoma
6. Lymphomas of other histologies other than the ones listed in section 3.3 above
7. Follicular lymphoma with large cell transformation
8. Decompensated liver disease in which pegylated interferon is contraindicated.
9. Female who is pregnant or breast feeding and HCV treatment requires use of ribavirin.
10. Solid organ transplant
11. 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
12. Known hypersensitivity to ledipasvir, sofosbuvir, or formulation excipients.
13. On a prohibited medication which cannot be stopped during the duration of HCV treatment.
14. Female subject who is pregnant or breastfeeding
15. HIV-infection