E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsed or refractory Non-Hodgkin Lymphoma and relapsed or refractory Diffuse Large B-cell Lymphoma. |
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E.1.1.1 | Medical condition in easily understood language |
Non-Hodgkin Lymphoma and Diffuse Large B-cell Lymphoma |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the safety of Entospletinib (ENTO) with vincristine (VCR) in subjects with relapsed or refractory NHL |
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E.2.2 | Secondary objectives of the trial |
•The safety and efficacy of ENTO with vincristine (VCR) in subjects with relapsed or refractory B-cell NHL. •Attain the minimally effective or the recommended phase 2 expansion dose of ENTO in combination with VCR in adult subjects with relapsed or refractory B-cell NHL. •To evaluate the safety and therapeutic response to ENTO when administered in combination with VCR in the dose expansion stage in adult subjects with relapsed or refractory DLBCL. • To evaluate the safety of ENTO when administered in combination with VCR in the dose expansion stage in adult subjects with relapsed or refractory B-cell NHL (histologies other than DLBCL) • To evaluate therapeutic response to ENTO when administered in combination with VCR in the dose expansion stage in adult subjects with relapsed or refractory B-cell NHL (histologies other than DLBCL)
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) Subjects ≥ 18 years of age 2) Measurable disease by computed tomograph (CT)/ and/or positron-emission tomography CT (PET-CT) 3) A) Dose Escalation Stage: Confirmed Diagnosis of relapsed or refractory Non-Hodgkin Lymphoma (NHL) treated prior treatment for lymphoid malignancy comprising of at least 1 regimen containing a therapeutic anti-CD20 antibody (eg, rituximab, ofatumumab, GA-101) and at least 2 prior combination chemotherapy regimens or autologous stem cell transplant, or treated with 1 prior combination chemotherapy regimen in patients without an approved second-line therapy option, requiring treatment in the opinion of the treating physician B) Phase 2 Dose Expansion Cohorts: i) Expansion Cohort A: Diagnosis of relapsed or refractory DLBCL treated with prior treatment for lymphoid malignancy comprising of at least 1 regimen containing a therapeutic anti-CD20 antibody (eg, rituximab, ofatumumab, GA-101) and at least 2 prior combination chemotherapy regimens or autologous stem cell transplant, or treated with 1 prior combination chemotherapy regimen in patients without an approved second-line therapy option, requiring treatment in the opinion of the treating physician. ii) Expansion Cohort B: Diagnosis of relapsed or refractory B-cell NHL (other than DLBCL) treated with prior treatment for lymphoid malignancy comprising of at least 1 regimen containing a therapeutic anti-CD20 antibody (eg, rituximab, ofatumumab, GA-101) and at least 2 prior combination chemotherapy regimens or autologous stem cell transplant, or treated with 1 prior combination chemotherapy regimen in patients without an approved second-line therapy option, requiring treatment in the opinion of the treating physician 4) Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 or Karnofsky performance status ≥ 70 5) Adequate organ function defined by the screening laboratory inclusion listed below and Left Ventricular Ejection Fraction (LVEF) ≥ 45% confirmed by ECHO or MUGA |
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E.4 | Principal exclusion criteria |
1) Dose Expansion phase (Cohorts A – C): Diagnosis of lymphoma histologies other than DLBCL 2) Diagnosis of Primary Mediastinal Large B-cell Lymphoma 3) A life threatening illness, medical condition or organ system dysfunction which, in the investigator’s opinion, could compromise the subject’s safety or interfere with the absorption or metabolism of ENTO 4) Active or symptomatic CNS disease or epidural involvement 5) Uncontrolled intercurrent illness including, but not limited to, unstable angina pectoris or psychiatric illness/social situations that would limit compliance with study requirements 6) Current/ongoing neuropathy (sensory or motor) Grade > 1 or any history of Grade ≥ 3 neuropathy with prior VCR or chemotherapy exposure (documentation by history is adequate to exclude) 7) Contraindication to receive VCR or any planned protocol-specified chemotherapy 8) Eligible for autologous stem cell transplant 9) History of myelodysplastic syndrome, allogeneic stem cell or solid organ transplantation 10) History of any other non-lymphoid malignancy other than the registrational histology or any other non-lymphoid malignancy except for the following: adequately treated local basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder cancer, asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy or requiring only hormonal therapy and with normal prostate specific antigen for ≥ 1 year prior to the start of study drug, or any other cancer that has been in complete remission without treatment for ≥ 5 years prior to enrollment |
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E.5 End points |
E.5.1 | Primary end point(s) |
Occurrence of adverse events and laboratory abnormalities defined as DLTs for ENTO in combination with VCR in subjects in the dose escalation stage with relapsed or refractory NHL |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. For dose escalation stage, incidence of adverse events defined as dose limiting toxicities (DLTs) for ENTO in combination with VCR in participants with relapsed or refractory NHL [Time Frame: Up to 28 days] 2. For dose escalation stage, incidence of laboratory abnormalities defined as dose-limiting toxicities (DLTs) for ENTO in combination with VCR in participants with relapsed or refractory NHL [Time Frame: Up to 28 days] |
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E.5.2 | Secondary end point(s) |
Safety:
1 .Occurrence of adverse events and laboratory abnormalities not defined as DLTs for ENTO with VCR in subjects in the dose escalation stage with relapsed or refractory B-cell NHL
2. Occurrence of adverse events and laboratory abnormalities for ENTO with VCR in subjects of Cohort A in dose expansion stage with relapsed or refractory DLBCL
3.Occurrence of adverse events and laboratory abnormalities for ENTO with VCR in subjects in the dose expansion stage with relapsed or refractory B-cell NHL (non-DLBCL)
Efficacy:
4.Objective response rate (ORR) will be determined from the subjects’ best response during therapy of ENTO with VCR and VCR-based combination chemotherapy and will include complete response (CR) or partial response (PR)
5. Progression free survival (PFS) will be defined as the interval from the first dose of ENTO to the earlier of the first documentation of definitive disease progression or death from any cause
6. Overall survival (OS) will be defined as the interval from the start of study treatment to death from any cause.
7. Duration of response (DOR) will be defined as time from the first response (CR or PR) is achieved until the earlier of the first documentation of definitive disease progression or death from any cause
8. Time to response (TTR) will be defined as time from the first dose of ENTO to the first time the response (CR or PR) is achieved
Exposure: 9. Drug administration and duration of exposure of study treatment |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1.[Time Frame: Up to 6 months plus 30 days] 2. [Time Frame: Up to 6 months plus 30 days] 3.[Time Frame: Up to 6 months plus 30 days] 4. [Time Frame: Up to 6 months plus 5 years] 5. [Time Frame: Up to 6 months plus 5 years] 6. [Time Frame: Up to 6 months plus 5 years] 7. [Time Frame: Up to 6 months plus 5 years] 8. [Time Frame: Up to 6 months plus 5 years] 9. [Time Frame: Up to 6 months] 10. [Time Frame: Up to 6 months] |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Dose Escalation and Dose Expansion study |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 0 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 23 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Canada |
France |
Germany |
Hungary |
Italy |
Spain |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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End of study will be defined when the last patient reaches the last scheduled follow-up timepoint, is lost to follow-up, withdraws from the study, dies, or the time at which the Sponsor closes the study. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 8 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 8 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |