Daratumumab Plus Gemcitabine, Dexamethasone, Cisplatin in pt R/R CD38+ PTCL-NOS, AITL and TFH

Relapsed T-Cell Lymphoma Clinical Trial

Official title: A Phase II, Open Label, Multicenter Trial of Daratumumab in Combination With Gemcitabine, Dexamethasone and Cisplatin (D-GDP) in Patients With Relapsed/Refractory CD38 Positive Peripheral T-cell Lymphoma Not Otherwise Specified (PTCL-NOS), Angioimmunoblastic T-cell Lymphoma (AITL) and Other Nodal Lymphomas of TFH Cell Origin

Status Active, not recruiting

Clinical Trial Summary

FIL_Dara-GDP is a phase II, open label, multicenter clinical trial. The sponsor of this clinical trial is Fondazione Italiana Linfomi (FIL). The primary objective is to evaluate the efficacy of 4 courses of D-GDP (Daratumumab in combination with Gemcitabine, Cisplatin, Dexamethasone) in terms of complete response in patients with peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL) and other nodal lymphomas of T follicular helper cells (TFH cells) origin refractory/relapsed after at least one and no more than two previous lines of therapy.

Clinical Trial Description

This is an open-label, multicenter, single arm, single-stage phase II trial. After the patient signs the written informed consent the patient will enter the screening phase planning baseline assessments and a concomitant upfront confirmation of diagnosis of Peripheral T-Cell Lymphoma Not Otherwise Specified (PTCL-NOS), Angioimmunoblastic T-cell lymphoma (AITL) or Nodal Lymphoma of T Follicular Helper cells (TFH cells) origin and a central evaluation of immunohistochemical positivity of CD38 (cluster of differentiation 38) on bioptic material used to perform local diagnosis of relapsed disease, or that used for the more recent biopsy in the case of refractory patients. A core needle biopsy is considered sufficient for review and CD38 evaluation. Evaluation at central laboratory can be performed in bone marrow sections in those patients with only bone marrow lymphoma infiltration.

Only patients with confirmed eligible diagnosis and a percentage of CD38 positive tumor cells ≥ 5% will be considered eligible for study treatment.

The treatment consists of an induction phase and a maintenance phase.

Induction phase:

4-6 courses (according to response after cycle 4 and to patient compliance) of D-GDP (Daratumumab in combination with Gemcitabine, Cisplatin, Dexamethasone) every 21 days pursuant to the following schedule:

• Daratumumab cycle 1: 8 mg/kg i.v. on day 2 and on day 9; cycle 2-6: 16 mg/kg i.v. on day 2 and day 9)

• Gemcitabine 1000 mg/sm i.v. day 1 and day 8 (gemcitabine on day 8 to be skipped in case of grade 3-4 toxicity)

• Cisplatin 75 mg/sm i.v. day 1

• Dexamethasone 40 mg i.v. or po days 1-2-3-4-9

• Granulocyte-colony stimulating factor (G-CSF) from day 3 to 6, and from day 10 to 13 (to be prolonged if necessary) After 4 courses of D-GDP (Daratumumab in combination with Gemcitabine, Cisplatin, Dexamethasone), patients in Complete Remission/Partial Remission (CR/PR) and eligible for allogeneic stem cell transplantation (allo-SCT) will be addressed to allo-SCT consolidation.

Otherwise, patients in Complete Remission (CR) will enter the maintenance phase at this point of the study.

Patients in Partial Remission (PR) (not eligible for allogeneic stem cell transplantation) or in Stable Disease (SD) after D-GDP x 4 cycles can receive 2 additional courses of D-GDP before maintenance or can move directly to maintenance, according to center choice (based on patient condition, performance status and quality of response).

Patients who respond (Complete Remission/Partial Remission) after 6 courses of induction phase (end of induction, EOI) and eligible to allogeneic stem cell transplantation (allo-SCT) will be addressed to allo-SCT consolidation.

Patients who respond to the induction phase (Complete Remission/Partial Remission) and are not eligible for allogeneic stem cell transplantation (allo-SCT) and patients in stable disease (SD) at the End Of Induction (EOI), will move to the maintenance phase.

Patients in Progressive disease (PD) at any time will discontinue treatment, as well as patients experiencing at any time unacceptable toxicity.

Maintenance phase:

starting 28 days after the beginning of cycle 4 or 6 (or, in case of toxicity grade > 1, after toxicity is resolved) and up to 24 cycles from start of D-GDP (Daratumumab in combination with Gemcitabine, Cisplatin, Dexamethasone) according to the following schedule:

• Daratumumab 16 mg/kg single administration every 28 days

Treatment with D-GDP (Daratumumab in combination with Gemcitabine, Cisplatin, Dexamethasone) or daratumumab single agent will be discontinued before completion of 24 cycles in case of:

• decision of the investigator to consolidate D-GDP (Daratumumab in combination with Gemcitabine, Cisplatin, Dexamethasone) response with allogeneic stem cell transplant

• disease progression

• unacceptable toxicity

• withdrawal of consent

• investigator determines that further therapy is not in the patient's best interest (e.g., due to non-compliance, toxicity, etc.) Adverse events ("Common Terminology Criteria for Adverse Events", CTCAE v. 5.0) will be monitored from the first study-related procedure, throughout treatment, maintenance and for 30 days after the end of treatment with the study drug.

Safety monitoring and stopping rules:

In order to monitor the safety and the activity of the treatment in small cohorts of patients, the Bayesian approach of Thall et al. (1995), as extended by Thall and Sung (1998) will be used.

Monitoring of relevant toxicity after 4 cycles of D-GDP (Daratumumab in combination with Gemcitabine, Cisplatin, Dexamethasone) will be done to ensure that it is not higher than an acceptable toxicity of 30% (as defined in the safety endpoints) and the monitoring of activity after 4 cycles of D-GDP (Daratumumab in combination with Gemcitabine, Cisplatin, Dexamethasone) will be done to ensure that Complete Remission (CR) proportion is not lower than 40%.

The prior probability of toxicity and activity are modeled by beta distributions [Beta (0.6,1.4) and Beta (0.8,1.2), respectively].

The enrolment will be stopped if the posterior probability of the treatment being more toxic or less active than expected is greater than 95%.

The primary efficacy analysis will be performed after enrolment of 35 patients. The primary efficacy analysis will consist of an estimate of Complete Remission Rate (CRR) on the efficacy population after 4 cycles of D-GDP (Daratumumab in combination with Gemcitabine, Cisplatin, Dexamethasone) therapy, with 90% confidence intervals (according to 1-sided alpha error of 0.05). To conclude that the new treatment is promising, the minimum number of patients with a Complete Remission (CR) is 12/35.

The time-to-event functions (Overall Survival (OS) and Progression Free Survival (PFS)) will be estimated by the Kaplan-Meier product-limit method.

Subgroup analyses on primary efficacy parameter (Complete Remission Rate (CRR)) will be performed to assess the role of daratumumab maintenance and to explore potential prognostic role of CD38 expression. A logistic regression model will be used and the effect (Complete Remission Rate (CRR)) and its 95% Interval of Confidence (CI) will be presented.

For safety analysis, both at patient level and at therapy cycle level, summaries of incidence rates (frequencies and percentages) and intensity of individual adverse events by CTCAE (Common Terminology Criteria for Adverse Events (CTCAE)) v. 5.0 will be reported.

The results of this study will support the rationale of a phase III randomized trial if both efficacy and safety endpoints will be considered promising. ;

Related Conditions & MeSH terms

• Lymphoma
• Lymphoma, T-Cell
• Lymphoma, T-Cell, Peripheral
• Refractory T-Cell Lymphoma
• Relapsed T-Cell Lymphoma

• NCT number: NCT04251065
• Study type: Interventional
• Source: Fondazione Italiana Linfomi ONLUS
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: September 3, 2020
• Completion date: November 15, 2022