To Assess the Safety and Tolerability of Tafasitamab Alone or in Combination With Other Drugs in Japanese Participants With Non-Hodgkins Lymphoma (NHL)

Study Overview
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Brief Summary
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This is an open-label, multicenter study to evaluate safety and tolerability, determine the RP2Ds of tafasitamab alone in Japanese participants with R/R NHL, or to evaluate efficacy and safety of tafasitamab in combination with lenalidomide in Japanese participants with R/R DLBCL, or tafasitimab in combination with lenalidomide plus R-CHOP in Japanese participants with previously untreated DLBC, or tafasitimab in combination with lenalidomide in Japanese participants with previously R/R DLBC.

Official Title
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A Phase 1b/2 Study of Tafasitamab, Tafasitamab Plus Lenalidomide, Tafasitamab Plus Parsaclisib, and Tafasitamab Plus Lenalidomide in Combination With R-CHOP in Japanese Participants With Non-Hodgkin Lymphoma

Conditions
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Non Hodgkins Lymphoma, Diffuse Large B-cell Lymphoma

Intervention / Treatment
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* Drug: tafasitamab
* Drug: lenalidomide
* Drug: parsaclisib
* Drug: R-CHOP


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Groups 1 and 2 only: Biopsy-proven participants with relapsed or refractory NHL of DLBCL, FL or MZL.. Groups 3, and 4 only: Biopsy-proven participants with relapsed or refractory DLBCL. Groups 5 only: Biopsy-proven participants with relapsed or refractory DLBCL.. Group 6 only: Biopsy-proven participants with DLBCL and another select lymphoid neoplasms. Participants must have at least 1 bi-dimensionally measurable lesion. -ECOG performance status of 0 to 2. Participants with protocol defined laboratory criteria at screening Groups 1 and 2 only: Received at least 1 previous systemic therapy line for the treatment of NHL. At least 1 previous therapy line must have included a CD20-targeted therapy (eg, RTX). -Groups 3, 4a, and 4b and 6only: Received at least 1, but no more than 3, previous systemic therapy lines for the treatment of DLBCL. At least 1 previous therapy line must have included a CD20-targeted therapy (eg, RTX). - Group 5 only: Participants must have: a. Untreated DLBCL. b. Ann Arbor Stage III to IV. c. IPI status of 3 to 5 or age-adjusted IPI 2-3 (in Group 5 only). d. Appropriate candidate for R-CHOP. e. LVEF of ≥ 50%, assessed by echocardiography. -Willingness to avoid pregnancy or fathering children. -In the opinion of investigator, the participant must: a. Not have a history of noncompliance in relation to medical regimens or be considered potentially unreliable and/or uncooperative. b. Be able to understand the reason for complying with the special conditions of the pregnancy prevention risk management plan and give written acknowledgement of this. Exclusion Criteria: -Any other histological type of lymphoma Group 6 only: Primary refractory DLBCL History of prior non-hematologic malignancy Congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias. Participants with known positive test result for hepatitis C, and hepatitis B. Known seropositive for or history of active viral infection with HIV. Known active bacterial, viral, fungal, mycobacterial, or other infection at screening. Known CNS lymphoma involvement - present or past medical history. 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. History or evidence of rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption. History or evidence of interstitial lung disease. Vaccination with live vaccine within 21 days prior to study treatment (Note: throughout the study treatment period and at least 6 months after end of treatment, vaccination with live vaccines should be avoided). Major surgery within up to 30 days prior to signing the ICF, unless the participant is recovered at the time of signing the ICF. Any anticancer and/or investigational therapy within 14 days prior to the start of Cycle 1 Groups 3, 4a, 4b, 5 and 6 only: Gastrointestinal abnormalities including the inability to take oral study treatment, requiring IV alimentation, or prior surgical procedure affecting absorption. Pregnancy or lactation. Groups 3, 5 and 6 only: Participants who have history of deep venous thrombosis/embolism, threatening thromboembolism, stroke or known thrombophilia or are at a high risk for a thromboembolic event in the opinion of the investigator and who are not willing/able to take venous thromboembolic event prophylaxis during the entire treatment period if required Groups 4a and 4b only: Use or expected use during the study of any restricted medications, including potent CYP3A4 inhibitors or inducers within 14 days or 5 half-lives (whichever is longer) before the date of study treatment administration Groups 1, 2, 3, 4a, and 4b only: Participants who have: a. Not discontinued CD20-targeted therapy, chemotherapy, radiotherapy, investigational anticancer therapy, or other lymphoma-specific therapy within the 14 days prior to Day 1 dosing. b. In the opinion of the investigator, not recovered sufficiently from the adverse toxic effects of prior therapies. c. Previous treatment with CD19-targeted therapy (eg, CD19-CAR-T therapies, other CD19 mAbs including bispecific and ADCs). d. Group 3 only: Been previously treated with IMiDs (eg, thalidomide or LEN). e. Group 4a and 4b only: Been previously treated with selective PI3Kδ or pan-PI3K inhibitors (eg, idelalisib, copanlisib, duvelisib) and/or Bruton's tyrosine kinase inhibitors (eg, ibrutinib). f. A history of hypersensitivity to compounds of similar biological or chemical composition to tafasitamab, IMiDs, and/or the excipients contained in the study treatment formulations (citric acid monohydrate, polysorbate 20, sodium citrate dehydrate and trehalose dihydrate). g. Undergone ASCT within the period ≤ 3 months before the signing of the ICF. Participants who have a more distant history of ASCT must exhibit full hematological recovery before enrolment into the study. h. Undergone previous allogenic stem cell transplantation. i. Concurrent treatment other anticancer or experimental treatments. Group 5 only: Participants who have: a. A history of radiation therapy to ≥ 25% of the bone marrow for other diseases or history of anthracycline therapy. b. A history of hypersensitivity or contraindication to any component of R-CHOP, LEN, or compounds of similar biological or chemical composition as tafasitamab and/or the excipients contained in the study treatment formulations or R-CHOP. c. Contraindication to any of the individual components of R-CHOP. d. Any anticancer and/or investigational therapy within 30 days prior to the start of Cycle 1, except for permitted prephase treatment defined below.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 : tafasitimab monotherapy<br>Dose-finding to evaluate the safety and tolerability and to determine the RP2Ds of single-agent tafasitamab in Japanese participants with NHL. Part 1 consists of 2 groups: Group 1 will evaluate weight-based doses of tafasitamab, and Group 2 will evaluate fixed doses of tafasitamab. | Drug: tafasitamab<br>* tafasitamab will be administered at protocol defined timepoints based on the groups participants are assigned.<br>* Other names: Xmab5574;|
| Experimental: Part 2 : tafasitamab combination therapy<br>tafasitamab will be combined with lenalidomide (Group 3) or parsaclisib (Group 4a) in R/R DLBCL participants or lenalidomide plus R-CHOP (Group 5) in previously untreated DLBCL participants. The dose of tafasitamab will be based on the weight-based RP2D that is deemed safe and tolerable in Part 1. | Drug: tafasitamab<br>* tafasitamab will be administered at protocol defined timepoints based on the groups participants are assigned.<br>* Other names: Xmab5574;Drug: lenalidomide<br>* lenalidomide will be administered orally at protocol defined timepoints based on the groups participants are assigned.<br>Drug: parsaclisib<br>* parsaclisib will be administered at protocol defined timepoints based on the groups participants are assigned.<br>Drug: R-CHOP<br>* R-CHOP is a combination regimen consisting of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone. R-CHOP will be administered at protocol defined timepoints based on the groups participants are assigned.<br>|
| Experimental: Part 3 : Dose Expansion of tafasitamab +parsaclisib<br>tafasitamab in combination with parsaclisib will be further evaluated in Group 4b at RP2D determined in Part 2 | Drug: tafasitamab<br>* tafasitamab will be administered at protocol defined timepoints based on the groups participants are assigned.<br>* Other names: Xmab5574;Drug: parsaclisib<br>* parsaclisib will be administered at protocol defined timepoints based on the groups participants are assigned.<br>|
| Experimental: Part 4: tafasitamab combination therapy<br>tafasitamiab in combination with lenalidomide will be further evaluated in Group 6 at RP2D determined in Part 2. | Drug: tafasitamab<br>* tafasitamab will be administered at protocol defined timepoints based on the groups participants are assigned.<br>* Other names: Xmab5574;Drug: lenalidomide<br>* lenalidomide will be administered orally at protocol defined timepoints based on the groups participants are assigned.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1,2 and 3 : Treatment Emergent Adverse Events (TEAE'S) | Adverse events reported for the first time or worsening of a pre-existing event after first dose of study treatment. | Approximately 2 years | 
| Part 4: Objective Response | Best Response of complete/complete metabolic response or partial/partial metabolic response | Approximately 27 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1,2, 3 and 4 : Cmax of tafasitamab | Maximum observed serum concentration. | Approximately 27 months | 
| Part 1, 2, 3 and 4: Cmin of tafasitamab | Minimum observed serum concentration over the dose interval. | Approximately 27 months | 
| Part 4: Complete Response | Defined as the proportion of participants with Complete Response as determined by an IRC and investigator assessment according to the Lugano criteria | Approximately 27 months | 
| Part 4: Duration of Response | Defined as the time from the date of first documented evidence of CR or PR until the first documented disease progression or death from any cause, whichever occurs first, among participants who achieve an objective response as determined by IRC and investigator assessment based on the Lugano criteria for response assessment | Approximately 27 months | 
| Part 4: Progression-Free Survival | Defined as the time from the date of randomization until the first documented disease progression as determined by IRC and investigator assessment based on the Lugano criteria for response assessment or death from any cause, whichever occurs first. | Approximately 27 months | 
| Part 4: Overall Survival | Defined as the time from the date of randomization until death from any cause. | Approximately 27 months | 
| Part 4: Overall Response Rate | Defined as the proportion of participants with a CR or PR as determined by the investigator based on the Lugano criteria for response assessment | Approximately 27 months | 
| Part 4: Treatment Emergent Adverse Events (TEAE'S) | Adverse events reported for the first time or worsening of a pre-existing event after first dose of study treatment. | Approximately 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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INCMOR00208, tafasitamab