Study of Entospletinib (ENTO) in Newly Diagnosed DLBCL Patients With aaIPI>=1 Treated by Chemiotherapy

DLBCL Clinical Trial

Official title:

Phase Ib - II Study of Entospletinib (ENTO) in Newly Diagnosed Diffuse Large B Cell Lymphoma (DLBCL) Patients With aaIPI>=1 Treated by Rituximab, Cyclophosphamide, Hydroxydaunomycin, Oncovin, and Prednisone (R-CHOP)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03225924
• Other study ID #: ENTO-R-CHOP
• Status: Terminated
• Phase: Phase 1/Phase 2
• Start date: July 26, 2017
• Est. completion date: October 18, 2019

Study information

• Verified date: September 2020
• Source: The Lymphoma Academic Research Organisation
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The primary objective of the phase Ib of the study is to determine the recommended phase 2 dose (RP2D) for entospletinib (ENTO) in patients treated with R-CHOP.

The primary objective of the phase II is to determine the complete metabolic response (CMR) rate by the Lugano classification 2014 (Deauville scale 1-3) at the end of treatment.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 25
• Est. completion date: October 18, 2019
• Est. primary completion date: October 18, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 60 Years to 80 Years

Eligibility

Inclusion Criteria:

1. Patients with histologically confirmed de novo DLBCL (CD20 positive) (cf section 20.6

• Appendix 4)

2. Age between 60 and 80 years included, on the day of the informed consent document signature

3. Age adjusted International Prognosis Index (aaIPI) score = 1

4. No prior treatment for DLBCL. However prephase treatment with 1mg/kg/day prednisone or equivalent, for a maximum of 14 days, is permitted prior to begin the treatment

5. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 (0 or 1 only for phase 1b)

6. Life expectancy of = 90 days (3 months) before starting Entospletinib

7. Signed informed consent

8. At least one bi-dimensionally measurable lesion defined as at least one node or tumor lesion on CT scan = 1.5 cm

9. fluorodeoxyglucose (FDG) positron emission tomography (PET-CT) performed at baseline with a FDG positive result

10. Adequate hematologic functions defined as follows (unless secondary to bone marrow involvement by lymphoma):

• Absolute neutrophil count (ANC) > 1.5 X 10^9 G/l and

• Platelets count = 75 X 10^9/l without platelet transfusion dependency during the last 7 days and

• Haemoglobin level > 9 g/dl (may receive transfusion)

11. Adequate liver function defined as follows:

• Total bilirubin <1.5 upper limit of normal (ULN) except for unconjugated hyperbilirubinemia of Gilbert's syndrome and

• Alkaline phosphatase (in absence of bone disease), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 3 X ULN

12. Adequate renal function as calculated by a creatinine clearance > 40 ml/min by local institutional formula

13. Patients with prior Hepatitis B must be given antiviral prophylaxis and hepatitis B virus (HBV) DNA monitored; Patients with prior Hepatitis C are eligible if, hepatitis C virus (HCV) RNA is undetectable.

14. Left ventricular ejection fraction (LVEF) = 50% of echocardiography or multiple gated acquisition (MUGA) scan

15. Adequate tissue for central retrospective testing for cell of origin (10-15 slides of tumor biopsy must be available at baseline)

16. Heterosexually active females of childbearing potential (as defined in the protocol) must:

• have a negative serum pregnancy test at baseline and prior to the first study drug administration (C1D-4)

• have practiced at least 1 reliable method of contraception for at least 2 months prior to the first study drug administration (C1D-4)

• agree to utilize highly effective methods of contraception (as defined in the protocol) from Cycle 1 Day -4 until 12 months following the last treatment administration

17. Heterosexually active males with partners of childbearing potential must agree to use reliable forms of contraception during treatment and up to 12 months after last treatment administration

18. Male subjects must agree to avoid sperm donation from Cycle 1 Day -4 until 12 months following the last treatment administration

Exclusion Criteria:

1. Central nervous system or meningeal involvement with DLBCL

2. Contraindication to any drug contained in the chemotherapy regimen

3. Prior treatment with Entospletinib or other spleen tyrosine kinase (SYK ) inhibitor

4. Patients with a prior history of other malignancy, exceptions include:

• a subject who has been disease-free after curative local treatment (surgical resection) for at least 3 years,

• a subject with a history of a completely resected non-melanoma skin cancer or in situ carcinoma with surgical complete excision.

5. Patients taking current therapy with proton pump inhibitors and current therapy with medicines that are strong Cytochrome P450 3A (CYP3A) or CYP2C9 inducers, or moderate CYP2C9 inducers.

6. Ongoing active pneumonitis

7. Peripheral sensory or motor neuropathy grade > 1.

8. Major surgery within 4 weeks before first dose of study drug (minor procedures including transcutaneous biopsy, central line placement are permitted at any time)

9. Inability to take oral medication or malabsorption syndrome or any other uncontrolled gastrointestinal condition that would impair ability to take entospletinib

10. Significant cardiovascular impairment: congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction or stroke within 6 months of first dose of entospletinib or ventricular arrhythmia

11. Active infection as judged by the investigator

12. Known hypersensitivity to ENTO

13. Congenital immunodeficiency or known HIV (human immunodeficiency virus infection) or active viral hepatitis B or C

14. Any other major illness that in the investigator's judgement, will substantially increase the risk associated with the subject's participation in the study

15. Subjects who have undergone a solid organ transplant and stem cell transplant

16. Previous treatment for B cell lymphoma or Richter's transformation

17. Primary Mediastinal B Cell Lymphoma

Related Conditions & MeSH terms

• DLBCL
• Lymphoma, Large B-Cell, Diffuse

Intervention

Drug:
• Entospletinib
200mg or 400mg twice a day for 7 days every 21 cycles - total of 8 cycles
• Rituximab
cycles of 21 days - 375mg/m²
• Cyclophosphamide
cycles of 21 days - 750 mg/m²
• Doxorubicin
cycles of 21 days - 50mg/m²
• Vincristine
cycles of 21 days - 1.4mg/m²
• Prednisone
cycles of 21 days - 40mg/m²

Locations

Country	Name	City	State
Belgium	Clinique Universite Catholique de Louvain Saint-Luc	Bruxelles
Belgium	Institut Jules Bordet	Bruxelles
Belgium	University Hospital Gent	Gent
Belgium	Hopital Joliment	Haine-Saint-Paul
Belgium	Az Groeninge	Kortrijk
Belgium	UCL Namur	Yvoir
France	Ch de Bourg En Bresse	Bourg-en-Bresse
France	CHU Côte de Nacre	Caen
France	CHU Henri Mondor	Créteil
France	CHU de Dijon	Dijon
France	Ch de Versailles - Hopital Andre Mignot	Le Chesnay
France	Clinique Victor Hugo	Le Mans
France	Chu de Limoges - Hopital Dupuytren	Limoges
France	CHU Lyon Sud	Lyon
France	Clinique de La Sauvegarde	Lyon
France	CHU Montpellier	Montpellier
France	Ch Region Mulhouse Et Sud Alsace	Mulhouse
France	Hopital Necker Paris	Paris
France	Chu de Bordeaux	Pessac
France	Ch Annecy Genevois	Pringy
France	Chu de Reims - Hopital Robert Debre	Reims
France	Chu de Rennes - Pontchaillou	Rennes
France	Ch de Roubaix-Hopital Victor Provo	Roubaix
France	Iuct Oncopole de Toulouse	Toulouse
France	Hôpital Bretonneau- Centre H. Kaplan	Tours
France	Ch de Valenciennes	Valenciennes
France	Chru de Nancy	Vandœuvre-lès-Nancy

Sponsors (1)

Lead Sponsor	Collaborator
The Lymphoma Academic Research Organisation

Countries where clinical trial is conducted

Belgium,  France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Phase I: recommended phase 2 dose	To determine the recommended phase 2 dose for Entospletinib	6 months
Primary	Phase II: Complete Metabolic Response (CMR) rate at the end of treatment	To determine the CMR rate by the Lugano classification 2014 (Deauville scale 1-3) at the end of treatment	168 days