Trial comparing the efficacy and safety of tafasitamab plus lenalidomide in addition to standard therapy versus standard therapy in patients newly diagnosed with lymphoma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Incyte Corp.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

23 Apr 2021 → ongoing

Decision date (initial)

2024-04-24

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Incyte Corporation

External identifiers

EU CT number

2022-500237-92-00

EudraCT number

2020-002990-84

WHO UTN

U1111-1307-4207

ClinicalTrials.gov

NCT04824092

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Pharmacogenetic, Safety, Therapy, Others, Pharmacokinetic, Efficacy

To compare the efficacy of tafasitamab plus lenalidomide in addition to R-CHOP versus tafasitamab placebo, lenalidomide placebo and R-CHOP (henceforth referred to as R-CHOP in the context of the control arm).

Secondary objectives 8

1. To compare the efficacy (additional parameters) of tafasitamab plus lenalidomide in addition to R-CHOP versus R-CHOP.
2. To compare the safety of tafasitamab plus lenalidomide in addition to R-CHOP versus R-CHOP.
3. To compare the efficacy of tafasitamab plus lenalidomide in addition to R-CHOP versus R-CHOP in DLBCL subtypes of COO.
4. To compare the efficacy of tafasitamab plus lenalidomide in addition to R-CHOP versus R-CHOP in DLBCL subtypes: DLBCL NOS versus HGBL versus other.
5. To compare the incidence of central nervous system relapse in patients receiving tafasitamab plus lenalidomide in addition to R-CHOP versus R-CHOP.
6. To assess patient-reported outcomes in patients receiving tafasitamab plus lenalidomide in addition to R-CHOP versus R-CHOP.
7. To assess the pharmacokinetic profile of tafasitamab.
8. To assess the potential immunogenicity of tafasitamab.

Conditions and MedDRA coding

Newly-diagnosed high-intermediate and high-risk diffuse large B-cell lymphoma (DLBCL)

Study design 3 periods

Regulatory references

Scientific advice from competent authorities

Food And Drug Administration, European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-002499-PIP02-19

Plan to share IPD

Yes

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Signed written informed consent form (ICF).
2. Adult subjects aged 18 (or legal age per local regulations) to 80 years of age inclusive.
3. Previously untreated patients with local biopsy-proven, CD20-positive DLBCL, including one of the following diagnoses by 2016 World Health Organization (WHO) classification of lymphoid neoplasms are eligible: • DLBCL, NOS including GCB type, ABC type • T-cell rich large BCL • Epstein-Barr virus-positive DLBCL, NOS • Anaplastic lymphoma kinase (ALK)-positive large BCL • Human herpes virus-8 (HHV8)-positive DLBCL, NOS • High-grade BCL with MYC and B-cell lymphoma 2 (BCL2) and/or B-cell lymphoma 6 (BCL6) rearrangements (double-hit or triple-hit lymphoma). Please note: Patients must be appropriate candidates for R-CHOP. If an investigator deems a patient with a known double- or triple-hit lymphoma (HGBL) should be treated more aggressively (e.g. dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab [DA-EPOCH-R] or cyclophosphamide, vincristine, doxorubicin and dexamethasone (CVAD) followed by methotrexate and cytarabine [Hyper CVAD]), this patient would not be considered eligible for this study • HGBL-NOS • DLBCL coexistent with either FL of any grade, gastric mucosa-associated lymphoid tissue (MALT) lymphoma or non-gastric MALT lymphoma • FL Grade 3b
4. Availability of archival or freshly collected tumor tissue sent for retrospective central pathology review. Please note: Neither receipt of tumor samples nor central review of diagnosis is necessary prior to study enrollment.
5. Up to six (6) of the largest target nodes, nodal masses, or other lymphomatous lesions that are measurable in two (2) diameters should be identified by local assessment from different body regions representative of the patient’s overall disease burden and include mediastinal and retroperitoneal disease, if involved. At baseline, a measurable node must be greater than 15 mm in longest diameter (LDi). Measurable extranodal disease may be included in the six (6) representative, measured lesions. At baseline, measurable extranodal lesions should be greater than 10 mm LDi. All other lesions (including nodal, extranodal, and assessable disease) should be followed as nonmeasured disease as non-target lesions (e.g. cutaneous, GI, spleen, liver, kidneys, pleural or pericardial effusions, ascites, bone, bone marrow). Patients with ONLY bone lesions should be excluded. At least one (1) measurable lesion must be confirmed to be PET-positive (Deauville score of 4 or 5) at the time of randomization by local assessment.
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
7. IPI status of 3 to 5 (for patients > 60 years of age) or aaIPI 2 to 3 (for patients ≤ 60 years of age).
8. Diagnosis to treatment interval, defined as the time between the date of DLBCL diagnosis (date of the first biopsy specimen containing B-cell lymphoma according to the local pathology report) and the start of treatment (cycle 1 study day 1 (C1D1)) ≤ 28 days.
9. Left ventricular ejection fraction ≥ 50% as assessed by local echocardiography or cardiac multi-gated acquisition (MUGA) scan.
10. Patient must have the following local laboratory criteria at screening: a. Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L (unless secondary to bone marrow involvement by DLBCL) b. Platelet count ≥ 75 x 10^9/L (unless secondary to bone marrow involvement by DLBCL) c. Total serum bilirubin < 1.5 × upper limit of normal (ULN) unless secondary to Gilbert’s Syndrome or documented liver involvement by lymphoma. Patients with Gilbert’s Syndrome or documented liver involvement by lymphoma may be included if their total bilirubin is ≤ 5 × ULN d. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) ≤ 3 × ULN, or ≤ 5 × ULN in cases of documented liver involvement e. Serum creatinine clearance must be ≥ 30 mL/minute either measured or calculated using a standard Cockcroft and Gault formula (Cockroft and Gault, 1976)
11. In the opinion of investigator, the patient must: a. Be able and willing to receive adequate prophylaxis and/or therapy for thromboembolic events, e.g. aspirin 75 to 325 mg per os, orally (PO) daily (81 to 325 mg PO daily in the US) or low molecular weight heparin (e.g. enoxaparin 40 mg (4,000 IU) once daily by subcutaneous (SC) injection). This is due to increased risk of thrombosis in patients treated with lenalidomide without prophylaxis. Patients unable or unwilling to take any prophylaxis are not eligible b. Be able to understand, give written informed consent, and comply with all study-related procedures, medication use, and evaluations c. Not have a history of noncompliance in relation to medical regimens nor be considered potentially unreliable and/or uncooperative d. Be able to understand the reason for complying with the special conditions of the pregnancy prevention and in writing acknowledge to adhere to them
12. Due to the teratogenic potential of lenalidomide, females of childbearing potential (FCBP) must: a. Not be pregnant as confirmed by a negative serum pregnancy test at screening and a medically supervised urine pregnancy test prior to starting study therapy b. Refrain from breast feeding and donating oocytes during the course of study and for three (3) months after the last dose of study drug or according to local guidelines for R-CHOP, whichever is longer c. Agree to ongoing pregnancy testing during the course of the study and after study therapy has ended. Additionally, agree to pregnancy testing and counseling if a patient misses her period or if there is any abnormality in her menstrual bleeding. This applies even if the patient applies complete sexual abstinence d. Commit to continued abstinence from heterosexual intercourse if it is in accordance with her lifestyle (which must be reviewed on a monthly basis) or agree to use and be able to comply with the use of highly effective contraception without interruption at least four (4) weeks prior to start of study drugs, during the study treatment and for three (3) months after the last dose of study drug, or, for R-CHOP, according to the local guidelines, whichever is longer.
13. Male participants must: a. Use an effective barrier method of contraception without interruption if the patient is sexually active with a FCBP. Male participants should refrain from donating sperm during the study participation and for three (3) months after the last dose of study drug, or according to the local guidelines for R-CHOP, whichever is longer

Exclusion criteria 17

1. 1) Any other histological type of lymphoma according to WHO 2016 classification of lymphoid neoplasms, e.g. primary mediastinal (thymic) large B-cell lymphoma, Burkitt’s lymphoma, BCL, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma (grey-zone lymphoma); primary effusion lymphoma; primary cutaneous DLBCL, leg type; primary DLBCL of the CNS; DLBCL arising from CLL or indolent lymphoma.
2. 2) History of radiation therapy to ≥ 25% of the bone marrow for other diseases.
3. 3) History of prior non-hematologic malignancy except for the following: a. Malignancy treated with curative intent and with no evidence of active disease present for more than two (2) years before screening b. Adequately treated lentigo maligna melanoma without current evidence of disease or adequately controlled non-melanomatous skin cancer. c. Adequately treated carcinoma in situ without current evidence of disease.
4. 4a) Patients with positive local test result during screening for hepatitis C (hepatitis C virus [HCV] antibody serology testing) and a positive test for HCV RNA. Patients with positive serology must have been tested locally for HCV RNA and are eligible, in case of negative HCV RNA test results
5. 4b) Patients with positive local test result during screening for chronic hepatitis B virus (HBV) infection (defined by hepatitis B surface antigen [HBsAg] positivity). Patients with occult or prior HBV infection (defined as negative HBsAg and positive total hepatitis B core antibody [HBcAb]) may be included if HBV DNA was undetectable (local test result), provided that they are willing to undergo ongoing DNA testing. Patients who have protective titers of hepatitis B surface antibody (HBsAb) after vaccination or prior but cured hepatitis B are eligible
6. 4c) Patients with Seropositive (local test during screening) for, or history of active viral infection with human immunodeficiency virus (HIV)
7. 4d) Patients with known active systemic bacterial, viral, fungal, or other infection at screening, including patients with suspected active or latent tuberculosis (as confirmed by a positive interferon-gamma release assay). Antiviral or antibacterial prophylaxis may be administered as per institutional guidelines
8. 4e) Patients with positive results for the human T-lymphotropic 1 virus (HTLV-1). HTLV testing during screening is required for patients at sites in endemic countries (Japan and Melanesia and countries in the Caribbean basin, South America, Central America, and sub-Saharan Africa)
9. 4f) Patients with known CNS lymphoma involvement
10. 4g) Patients with history or evidence of clinically significant cardiovascular, CNS and/or other systemic disease that, in the investigator’s opinion, would preclude participation in the study or compromise the patient’s ability to give informed consent
11. 4h) Patients with history or evidence of rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption
12. 4i) Patients with vaccination with live vaccine within 21 days prior to study randomization
13. 4j) Patients with major surgery within up to 21 days prior to signing the informed consent form (ICF), unless the patient is recovered at the time of signing the ICF
14. 4k) Patients with any systemic anti-lymphoma and/or investigational therapy prior to the start of C1D1, except for permitted pre-phase treatment
15. 4l) Patients with contraindication to any of the individual components of R-CHOP, including prior receipt of anthracyclines
16. 4m) Patients with pregnancy or lactation
17. 4n) Patients with history of hypersensitivity to any component of R-CHOP, to lenalidomide, to compounds of similar biological or chemical composition to tafasitamab, IMiDs and/or the excipients contained in the study drug formulations

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Progression-free survival (PFS) is defined as time from date of randomization until Progressive Disease or death from any cause. In this trial the primary endpoint is PFS as assessed by the investigator. Disease progression will be determined based on the Lugano Response Criteria for Malignant Lymphoma (Cheson et al., 2014; Appendix F).

Secondary endpoints 25

1. Event-free survival (EFS) as assessed by the investigator
2. Overall survival (OS)
3. Metabolic, positron emission tomography (PET)-negative complete response (CR) rate at end of treatment (EOT) as assessed by the BIRC
4. Metabolic, PET-negative CR rate at EOT as assessed by the investigator
5. ORR at EOT as assessed by the investigator
6. Time to next anti-lymphoma treatment (TTNT)
7. Duration of CR as assessed by the investigator
8. EFS rate at three (3) years as assessed by the investigator
9. PFS rate at three (3) years as assessed by the investigator
10. OS rate at three (3) years
11. Incidence and severity of treatment emergent adverse events (TEAEs) from the first dose of study medication until the 90th day (inclusive) after last dose of study medication.
12. PFS as assessed by the investigator by COO subtype
13. Investigator-assessed EFS by COO subtype
14. OS by COO subtype
15. Metabolic, PET-negative CR rate at EOT as assessed by the BIRC by COO subtype
16. Metabolic, PET-negative CR rate at EOT as assessed by the investigator by COO subtype
17. PFS as assessed by the investigator by locally determined histological subtype
18. Investigator assessed EFS by locally determined histological subtype
19. OS by locally determined histological subtype
20. Metabolic, PET-negative CR rate at EOT as assessed by the BIRC by locally determined histological subtype
21. Metabolic, PET-negative CR rate at EOT as assessed by the investigator by locally determined histological subtype
22. Two (2)-year rate of relapse with CNS involvement, as assessed by the investigator
23. Health-related quality of life (HRQoL), using the European Organisation for the Research and Treatment of Cancer (EORTC) QLQ-C30 and Functional Assessment of Cancer Therapy for Patients with Lymphoma (FACT-Lym) standardized instruments
24. Serum concentration of tafasitamab at specific time points (trough and maximum plasma concentration (Cmax) levels)
25. Incidence of anti-tafasitamab antibody formation, titer determination of confirmed positive samples

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Placebo 4

Auxiliary 6

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Incyte Corp.

Sponsor organisation

Incyte Corp.

Address

1801 Augustine Cut Off

City

Wilmington

Postcode

19803-4404

Country

United States

Scientific contact point

Organisation

Incyte Corp.

Contact name

Clinical Trial Information

Public contact point

Organisation

Incyte Corp.

Contact name

Clinical Trial Information

Third parties 18

Locations

11 EU/EEA countries · 104 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 118 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

7 submissions — initial application plus substantial / non-substantial modifications