IN MIND (INCYTE)

Participants are eligible to be included in the study only if all of the following criteria apply:

1. Age ≥ 18 years.

2. Ability to comprehend and willingness to sign a written ICF for the study.

3. Histologically confirmed Grade 1, 2, or 3a FL or histologically confirmed nodal MZL, splenic MZL, or extranodal MZL of the MALT as assessed locally (Swerdlow et al 2016).

Note: Participants with gastric MZL and evidence of Helicobacter pylori must have a documented nonresponse to antibiotic therapy.

4. Willingness to avoid pregnancy or fathering children based on the criteria below.

a. Male participants with reproductive potential must agree to take appropriate precautions to avoid fathering children (with at least 99% certainty) from screening through 180 days (6 months) after the last dose of study treatment, even if they have

undergone a successful vasectomy, and must refrain from donating sperm during this period. Permitted methods that are at least 99% effective in preventing pregnancy (see APPENDIX A) should be communicated to the participants and their

understanding confirmed.

b. WOCBP participants:

− Must commit either to abstain continuously from heterosexual sexual intercourse or agree to take appropriate precautions to avoid pregnancy (by using 2 different methods of birth control with at least 99% certainty) starting at least 4 weeks before taking the study treatment, while taking the study treatment, during breaks (dose interruptions), and for at least 90 days (3 months) after stopping the study treatment. Permitted methods that are at least 99% effective in preventing pregnancy (see APPENDIX A) should be communicated to the participants and their understanding confirmed.

− Must have a negative serum pregnancy test at screening (within 10-14 days of the first study drug treatment) and before the first dose on Day 1 (within 24 hours of initiating treatment with lenalidomide).

− Agree to ongoing pregnancy testing during the course of the study; weekly during the first month of study drug treatment, then monthly thereafter for women with regular menstrual cycles or every 2 weeks for women with irregular menstrual cycles (even if true abstinence is the chosen method of birth control) up to and including the EOT visit.

− Must refrain from breastfeeding and donating oocytes during the course of study and for 180 days (6 months) after the last dose of study treatment.

c. A woman not considered to be of childbearing potential as defined in APPENDIX A is eligible.

Note: The participants should be informed about the option of donation and cryopreservation of germ cells before the study if applicable.

5. All participants must:

a. Have an understanding that lenalidomide could have a potential teratogenic risk.

b. Abstain from donating blood while taking study treatment and for 28 days after discontinuation of study treatment.

c. Not share study medication with another person.

d. Agree to be counseled about pregnancy precautions and risk of fetal exposure.

e. In the opinion of the investigator, be able and willing to receive adequate mandatory prophylaxis and/or therapy for thromboembolic events (eg, aspirin 70-325 mg daily or low-molecular-weight heparin). Participants unable or unwilling to take any prophylaxis are not eligible.

f. In the opinion of the investigator, be able to understand and comply with all study-related procedures, medication use, and evaluations.

g. In the opinion of the investigator, not have a history of noncompliance or be considered potentially unreliable and/or uncooperative.

6. Tumor tissue sufficient for retrospective central pathology review and correlative studies must be provided as an adjunct to participation in this study. If an archival specimen is not available, a fresh biopsy is required prior to randomization (refer to the Laboratory Manual). Note: a fresh biopsy must be considered if the relapse is within 24 months from the initial diagnosis to exclude transformed cases and potentially misdiagnosed cases.

7. Must have been previously treated with at least 1 prior systemic anti-CD20 immunotherapy or chemo-immunotherapy. This includes treatments such as the following: rituximab monotherapy or chemotherapy plus immunotherapy with rituximab

or obinutuzumab, with or without maintenance. Note: At least 6 doses of anti-CD20 immunotherapy must have been given in prior therapy. Note: Systemic therapy does not include, for example, local involved field radiotherapy for limited stage disease,

HBV/HCV therapy, or H pylori eradication.

8. Must have documented relapsed, refractory, or PD after treatment with systemic therapy.

a. Relapsed lymphoma: relapsed after initial response of CR to prior therapy.

b. Refractory lymphoma: achieved less than PR to the last treatment or achieved a CR or PR that lasted less than 6 months before lymphoma progression.

c. Progressive lymphoma: PD after initial response of PR or SD to prior therapy.

9. Must be in need of treatment for relapsed, refractory, or PD as assessed by the investigator according to GELF criteria (see APPENDIX G).

a. Participants must have at least 1 measurable disease site. A radiographically measurable lymphadenopathy is defined as at least 1 nodal lesion > 1.5 cm in longest diameter or at least 1 extranodal lesion > 1.0 cm in longest diameter (Cheson et al 2014). The lesion must be confirmed to be PET-positive at the latest at the time of randomization.

10. ECOG performance status of 0 to 2.

11. Participants with laboratory values at screening defined in Table 6. 

Participants are excluded from the study if any of the following criteria apply:

1. Women who are pregnant or breastfeeding.

2. Any histology other than FL and MZL or clinical evidence of transformed lymphoma by INV assessment.

3. History of radiation therapy to ≥ 25% of the BM for other diseases.

4. History of prior nonhematologic malignancy except for the following:

a. Malignancy treated with curative intent and with no evidence of active disease for more than 2 years before screening.

b. Adequately treated lentigo maligna melanoma without current evidence of disease or adequately controlled nonmelanomatous skin cancer.

c. Adequately treated carcinoma in situ without current evidence of disease.

5. History of congestive heart failure requiring the use of ongoing maintenance therapy for life-threatening arrhythmias.

6. Participants with:

a. Known positive test result for HCV (with anti-HCV serology testing) and a positive test for HCV RNA.

Note: Participants with positive serology must have been tested for HCV RNA and are eligible only in the case of negative HCV RNA.

b. Known positive test result for chronic HBV infection (defined by HBsAg positivity).

Note: Participants with occult or prior HBV infection (defined as negative HBsAg and positive total HBcAb) may be included if HBV DNA was undetectable, provided that they are willing to undergo monthly ongoing DNA testing. Antiviral prophylaxis may be administered as per institutional guidelines. Participants who have protective titers of HBsAb (HBsAb positive, HBcAb negative, and HBsAg negative) after vaccination or previously cured hepatitis B are eligible.

c. Known seropositive for or history of active viral infection with human immunodeficiency virus.

7. Active systemic infection.

8. Participants in a severely immunocompromised state.

9. Known CNS lymphoma involvement.

10. Uncontrolled intercurrent illness.

11. History or evidence of clinically significant cardiovascular, CNS, and/or other systemic disease that would, in the investigator's opinion, preclude participation in the study or compromise the participant's ability to give informed consent.

12. Life expectancy < 6 months.

13. History or evidence of rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

14. Major surgery (excluding lymph node biopsy) within 28 days prior to signing the ICF unless the participant is recovered at the time of signing the ICF.

15. Any systemic antilymphoma and/or investigational therapy within 28 days prior to the start of Cycle 1.

16. Prior use of lenalidomide in combination with rituximab.

17. History of hypersensitivity to compounds of similar biological or chemical composition to tafasitamab, immunomodulatory drugs, rituximab, other monoclonal antibodies, and/or the excipients contained in the study drug formulations.

18. Any condition that would, in the investigator's judgment, interfere with full participation in the study, including administration of study treatment and attending required study visits; pose a significant risk to the participant; or interfere with interpretation of study data. 

Research Nurse: Nicola Slawson (Ext No. 53062) Nicola.Slawson@nhs.net

Administrator: Tamaryn Louw