An Open Label, Phase 2 Study to Evaluate Activity and Safety of Daratumumab in combination with Bortezomib and Dexamethasone in patients with Relapsed or Refractory Plasmablastic lymphoma (DALYA trial)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fondazione Italiana Linfomi Ets

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

11 Jul 2022 → ongoing

Decision date (initial)

2025-01-08

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Janssen-Cilag SpA

External identifiers

EU CT number

2024-511635-94-00

EudraCT number

2020-000409-94

ClinicalTrials.gov

NCT04915248

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy, Safety

To evaluate the activity of daratumumab as single agent and in combination with bortezomib/dexamethasone in patients with relapsed or refractory Plasmablastic lymphoma (PBL), who are not eligible for autologous or allogeneic transplantation or experienced relapse after a prior autologous stem cell transplantation.

Secondary objectives 9

1. To evaluate the efficacy in terms of Progression-free survival (PFS).
2. To evaluate the efficacy in terms of Overall survival (OS).
3. To evaluate the efficacy in terms of Duration of response (DOR).
4. To evaluate the safety of daratumumab as single agent and in combination with bortezomib/dexamethasone.
5. To assess the role of daratumumab maintenance.
6. To evaluate the association between intensity of CD38 expression and response.
7. Objective of the biological study: To evaluate the effect of daratumumab/bortezomib on a) CD4 and CD8 T cell homeostasis; b) regulatory cells (MDSC and Treg) homeostasis; c) inflammatory cytokines profile.
8. Objective of the biological study: To evaluate the effect of daratumumab/bortezomib treatment on functional properties of HIV-specific, EBV-specific and CMV-specific T cells.
9. Objective of the biological study: To analyze the microenvironment of the PBL.

Conditions and MedDRA coding

Relapsed or Refractory Plasmablastic lymphoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Histologically confirmed plasmablastic lymphoma according to WHO 2017, CD38-positive by immunohistochemistry (≥5% of positive cells) Local diagnosis of PBL and local CD38 assessment ≥5% will suffice for enrollment and start of treatment.
2. Patients with plasmablastic lymphoma relapsed or refractory: - after at least one line of conventional-dose chemotherapy followed or not by autologous stem cell transplantation; - after at least one line of conventional-dose chemotherapy and not eligible for salvage autologous or allogeneic transplantation;
3. ECOG Performance Status ≤ 3;
4. Age ≥ 18 years;
5. Both HIV-negative and HIV-positive patients are eligible;
6. HIV infection responsive to ongoing cART (combination antiretroviral therapy);
7. At least one measurable disease lesion identifiable by imaging: - A nodal lesion must be at least 11 mm x 11 mm OR ≥ 16 mm in the greatest transverse diameter (regardless of short axis measurement). - An extranodal lesion must be at least 10 mm x 10 mm.
8. Women of childbearing potential (WOCBP) and men must agree to use effective contraception if sexually active. This applies for the time period between signing of the informed consent form and 7 months (for women) o 4 months (for men) after last administration of bortezomib or 6 months after last daratumumab dose, regardless of sex. A woman is considered of childbearing potential, i.e., fertile, following menarche and until becoming postmenopausal unless permanently sterile. Permanent sterilization methods include but are not limited to hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for continuous 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. The investigator or a designated associate is requested to advise the patient how to achieve highly effective birth control method (failure rate of less than 1%) e.g., intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner, and sexual abstinence. The use of condoms by male patients is required unless the female partner is permanently sterile. WOCBP must have two negative pregnancy tests as verified by the study doctor prior to starting study therapy and must agree to undergo monthly pregnancy testing during the course of the study and after end of study therapy if clinically indicated. This applies even if the subject practices complete abstinence from heterosexual contact.
9. Subject understands and voluntarily signs and dates an informed consent form approved by the National Ethics Committee (NEC), prior to the initiation of any screening or study-specific procedures
10. Subject must be able to adhere to the study visit schedule and other protocol requirements

Exclusion criteria 14

1. Histologic diagnosis different from confirmed plasmablastic lymphoma according to WHO 2017 and/or CD38 expression < 5% of positive cells
2. CNS involvement
3. Patients with known hypersensitivity to the investigational drug or to product components or severe allergic or anaphylactic reactions to humanized products
4. Subject has received any anti-cancer therapy including chemotherapy, immunotherapy, radiotherapy, investigational therapy including targeted small molecule agents within 14 days prior to the first dose of study drug
5. Concomitant Kaposi sarcoma; however, patients with only skin involvement of KS can be included.
6. Subject is: - Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]. Subjects with resolved infection (i.e., subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen [HBcAb] ± antibodies to hepatitis B surface antigen [HBsAb]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded. EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (HBsAb positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR - Known to be seropositive for hepatitis C (except in the setting of a sustained virologic response [SVR], defined as aviremia at least 12 weeks after completion of antiviral therapy)
7. Any history of another cancer during the last 5 years with the exception of non-melanoma skin tumors, in situ cervical carcinoma, or in situ breast cancer treated with curative intent with no history of metastatic disease.
8. Chronic or ongoing active infectious disease requiring systemic treatment such as, but not limited to, chronic renal infection, chronic chest infection with bronchiectasis or tuberculosis. Drugs for HIV treatment are allowed, as per local investigator prescription.
9. Active ongoing infection from SARS-CoV-2.
10. Screening laboratory values (due to causes different than lymphoma): - Absolute neutrophil count (ANC) <1.0 x 109/L (unless secondary to documented marrow involvement by lymphoma) - Platelet count <75 x 109/L - Hemoglobin < 7.5 g/dL - Alanine aminotransferase (ALT) and/or Aspartate aminotransferase (AST) > 3.5 times the upper limit of normal (ULN) - Alkaline phosphatase > 3.5 times ULN - Bilirubin > 2 times x ULN (unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin) - Serum Creatinine Clearance < 20 ml/min
11. Subject has clinically significant cardiac disease, including: - Myocardial infarction within 6 months before date of registration, or unstable or uncontrolled disease/condition related to or affecting cardiac function (e.g., unstable angina, congestive heart failure, New York Heart Association Class III-IV) - Cardiac arrhythmia (Common Terminology Criteria for Adverse Events [CTCAE] current version Grade 2 or higher) or clinically significant ECG abnormalities. Screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia’s formula (QTcF) > 470 msec
12. Evidence of any other clinically significant uncontrolled condition(s)
13. Significant history of neurologic, psychiatric, endocrinological, metabolic, immunologic, or hepatic disease that would preclude participation in the study or compromise ability to give informed consent
14. Breastfeeding women or women with a positive pregnancy test at screening

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Overall Response Rate (ORR = Complete response, CR+ Partial response, PR) after induction cycle 1 (daratumumab alone), after induction cycles 3, 6 and 9 (end of induction, EOI); after maintenance cycles 12 and 15 (end of treatment, EOT). Response will be defined according to the Lugano 2014 criteria. The best response achieved per patient will be considered for analysis.

Secondary endpoints 8

1. Progression-free survival (PFS), defined as the time from treatment start and progression/relapse or death from any cause (Lugano 2014)
2. Overall survival (OS), defined as the time from treatment start and death from any cause (Lugano 2014).
3. Duration of response (DOR), defined for all patients who achieved a response (CR or PR) according to Response Criteria for NHL CT-based and/or PET-based (Lugano 2014), and is measured from the date when criteria for response are met (CR or PR) until the date of progression or relapse.
4. Role of daratumumab maintenance in terms of conversion rate of SD to PR or from SD/PR to CR.
5. Association between intensity of CD38 expression and response. The extent of CD38 expression evaluated by immunochemistry will be correlated with response measured according to the Lugano 2014 criteria at various timepoints.
6. Endpoints of the biological study: Impact of daratumumab/bortezomib treatment in immune activation, T cell differentiation, MDSC by multiparametric flow cytometry.
7. Endpoints of the biological study: Impact of daratumumab/bortezomib treatment on the level of pro- and anti-inflammatory cytokines by Luminex technology.
8. Endpoints of the biological study: Analysis of tumor microenvironment by ICH/alternative methods.

Investigational products

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

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fondazione Italiana Linfomi Ets

Sponsor organisation

Fondazione Italiana Linfomi Ets

Address

Piazza Filippo Turati 5

City

Alexandria

Postcode

15121

Country

Italy

Scientific contact point

Organisation

Fondazione Italiana Linfomi Ets

Contact name

Andrés Ferreri, Prof.

Public contact point

Organisation

Fondazione Italiana Linfomi Ets

Contact name

Andrés Ferreri, Prof.

Locations

1 EU/EEA country · 19 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 15 files

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

Application history

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