Clinical Trial Results:
Phase II study with Ga101-DHAP as induction therapy in relapsed/refractory Diffuse Large B-cell Lymphoma (DLBCL) patients before High-Dose chemotherapy BEAM with autologous stem cell transplantation (ASCT).
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Summary
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EudraCT number |
2013-004014-17 |
Trial protocol |
IT |
Global end of trial date |
23 Jun 2020
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Results information
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Results version number |
v1(current) |
This version publication date |
01 Apr 2022
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First version publication date |
01 Apr 2022
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
FIL_GA101_DHAP
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Additional study identifiers
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ISRCTN number |
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US NCT number |
NCT02374424 | ||
WHO universal trial number (UTN) |
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Sponsors
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Sponsor organisation name |
Fondazione Italiana Linfomi (FIL) ONLUS
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Sponsor organisation address |
Piazza Turati 5, Alessandria, Italy,
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Public contact |
Segreteria FIL ONLUS, Fondazione Italiana Linfomi (FIL) ONLUS, 0039 0131/033151, segreteriadirezione@filinf.it
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Scientific contact |
Segreteria FIL ONLUS, Fondazione Italiana Linfomi (FIL) ONLUS, 0039 0131/033151, segreteriadirezione@filinf.it
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Interim
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Date of interim/final analysis |
06 Feb 2018
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
06 Feb 2018
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Global end of trial reached? |
Yes
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Global end of trial date |
23 Jun 2020
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
Aim of this trial is to assess the efficacy of new anti-CD20 antibody (GA101) in association with DHAP as induction therapy before high dose chemotherapy BEAM with ASCT in patients with relapsed/refractory DLBCL.
Primary objective is to assess whether the treatment achieves an absolute increase of the CR proportion of at least 20% (from 30% to 50%) with respect to the standard treatment with an acceptable extra-hematological toxicity grade 3-4 of 0.25 (unacceptable extra-hematological toxicity=0.40).
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Protection of trial subjects |
The GA101 dose will be delayed or adjusted in case of:
- febrile neutropenia or neutropenia with infection;
- severe thrombocytopenia (platelets < 10,000/µL) and/or symptomatic bleeding in patients who are not receiving concomitant anticoagulants or platelet ihibitors;
- thrombocytopenia with platelets < 20,000/µL and/or symptomatic bleeding in patients who are receiving concomitant anticoagulants or platelet ihibitors
Patients must discontinue study drug if they experience any of the following:
- Pregnancy
- PML
- Grade 4 IRR
Patient should be withdrawn immediately and treatment must be discontinued permanently.
- Grade 3 IRR at re-challenge despite adequate premedication: patient must be withdrawn immediately and treatment must be discontinued permanently
- Grade 3 or 4 hematological toxicity that has not resolved to Grade ≤ 2 and requires to delay treatment by more that 14 days (Thrombocytopenia needs to resolve to Grade ≤1)
- Grade ≥ 2 non-hematological toxicity that does not resolve to Grade ≤ 1/baseline and requires to delay treatment by more that 14 days
- Hepatitis B reactivation
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Background therapy |
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Evidence for comparator |
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Actual start date of recruitment |
05 Nov 2014
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Italy: 29
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Worldwide total number of subjects |
29
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EEA total number of subjects |
29
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
29
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
Twenty-nine young patients recruited in Italy from 05 November 2014, with date of last completed at 25 January 2017. | ||||||||||||||||||
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Pre-assignment
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Screening details |
Patients with DLBCL who failed or relapsed after one previous chemotherapy regimen will be enrolled. All patients must satisfy all the inclusion criteria and none of exclusion criteria. | ||||||||||||||||||
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Period 1
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Period 1 title |
Baseline (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||
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Arms
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Arm title
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Single arm | ||||||||||||||||||
Arm description |
GA101-DHAP x 2 cycles (28 days), restaging, mobilization and harvest of peripheral stem cell + GA101-DHAP x 2, restaging with PET evaluation and consolidation with BEAM/FEAM and ASCT in responsive patients (CR + PR). GA101-DHAP scheme could be performed as in-patient or out-patient due to different organizational needs. No differences are reported in literature in term of efficacy of the two schemes. | ||||||||||||||||||
Arm type |
Single arm study | ||||||||||||||||||
Investigational medicinal product name |
Obinutuzumab (GA101)
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
GA101 will be administered by IV infusion as an absolute (flat) dose of 1000 mg on Day 1 of each 28-day cycle for 4 cycles. GA101 will be administered prior to DHAP, and patients should be observed 30 minutes prior to starting DHAP. If DHAP is not started or completed on Day 1 because of the long duration of GA101 therapy, DHAP chemotherapy may be administered on Day 2. During Cycle 1, GA101 will also be infused on Days 8 and 15.
GA101 1000 mg iv 24 hours before apheresis as purging in vivo during second courses of therapy.
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Investigational medicinal product name |
Cisplatin
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
In-patient version:
• 100 mg/sqm iv day 1 of every cycles in 24-hours infusion
Out-patient version:
• 100 mg/sqm iv day 1 of every cycles in 3-hours infusion
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Investigational medicinal product name |
Cytarabine
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
In-patient version:
• 2000 mg/sqm in 3-hours infusion every 12 hours iv day 2 of every cycles
Out-patient version:
• 2000 mg/sqm in 3-hours infusion iv day 2 and day 3 of every cycles
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Investigational medicinal product name |
Dexametasone
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
In-patient version:
• 40 mg day 1-4 of every cycles
Out-patient version:
• 40 mg day 1-4 of every cycles
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Investigational medicinal product name |
Pegfilgrastim
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
In-patient version:
• 6 mg sc single dose 24 hours after the end of chemotherapy or G-CSF from day 4 till stem cell harvest during mobilization’s course (II o III cycle GA101-DHAP)
Out-patient version:
• 6 mg sc single dose 24 hours after the end of chemotherapy or G-CSF from day 5 till stem cell harvest during mobilization’s course (II or III cycle GA101-DHAP)
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Baseline characteristics reporting groups
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Reporting group title |
Baseline
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Reporting group description |
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End points reporting groups
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Reporting group title |
Single arm
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Reporting group description |
GA101-DHAP x 2 cycles (28 days), restaging, mobilization and harvest of peripheral stem cell + GA101-DHAP x 2, restaging with PET evaluation and consolidation with BEAM/FEAM and ASCT in responsive patients (CR + PR). GA101-DHAP scheme could be performed as in-patient or out-patient due to different organizational needs. No differences are reported in literature in term of efficacy of the two schemes. | ||
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End point title |
Complete response rate (CR) [1] | ||||||||
End point description |
The complete response rate (CR) evaluated by PET scan after four cycles of GA101-DHAP before ASCT according to Cheson criteria. Historical data with which we will compare the results of our study were obtained in the same study population but with different response evaluation criteria (Cheson criteria 1999).
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End point type |
Primary
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End point timeframe |
After four cycles of GA101-DHAP before ASCT
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The study is single-arm without comparator. Historical data with which we will compare the results of our study were obtained in the same study population but with different response evaluation criteria (Cheson criteria 1999). |
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| No statistical analyses for this end point | |||||||||
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End point title |
Safety Evaluation [2] | ||||||||
End point description |
Severe, life-threatening, fatal (grade 3, 4 and 5) extra-hematological toxicity till one month after the last obinutuzumab administration (cycle 4), according to “Common Terminology Criteria for Adverse Events” CTCAE), version 4.0, are defined for primary toxicity evaluation.
Proportion of patients with non-hematologic toxicity (of grade 3 or greater).
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End point type |
Primary
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End point timeframe |
Till one month after the last obinutuzumab administration
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| Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The study is single-arm without comparator. The number of patients with non-haematological toxicities with grade> = 3 during experimental therapy should be less than 19 out of 29 patients. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Overall response rate (ORR) | ||||||||
End point description |
Overall response rate (ORR): a patient is defined as a responder if she/he has a complete or partial response, evaluated by PET/TC, after four cycles of GA101-DHAP.
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End point type |
Secondary
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End point timeframe |
Evaluated by PET/TC after four cycles of GA101-DHAP, prior to consolidation with BEAM and ASCT
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| No statistical analyses for this end point | |||||||||
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End point title |
The hematopoietic cell mobilization | ||||||||
End point description |
Mobilizing potential: amount of CD34 + stem cell collected /Kg
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End point type |
Secondary
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End point timeframe |
2 years
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| No statistical analyses for this end point | |||||||||
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End point title |
ASCT feasibility | ||||||||
End point description |
ASCT feasibility will be evaluated as the proportion of patients successfully completing ASCT.
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End point type |
Secondary
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End point timeframe |
2 years
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| No statistical analyses for this end point | |||||||||
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End point title |
Progression free survival (PFS) | ||||||||
End point description |
Progression free survival (PFS) is measured from the date of starting salvage therapy to the date of disease progression, relapse or death from any cause. Responding patients and patients who are lost to follow up will be surveyed at their last assessment date.
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End point type |
Secondary
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End point timeframe |
In the protocol at 6 month after the end of treatment (EOT); analyzed to 24 months from enrollment
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| No statistical analyses for this end point | |||||||||
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End point title |
Overall Survival (OS) | ||||||||
End point description |
Measured from the date of starting salvage therapy to the date of death from any cause. Patients alive at the time of the final analysis will be surveyed at the date of the last contact.
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End point type |
Secondary
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End point timeframe |
In the protocol 2 years after the EOT; analyzed 48 months after enrollment
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| No statistical analyses for this end point | |||||||||
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Adverse events information
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Timeframe for reporting adverse events |
From 5 November 2014 to 23 June 2020 (LPLV)
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Adverse event reporting additional description |
Grade>=3 toxicities
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
CTCAE | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
4
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Reporting groups
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Reporting group title |
Single arm
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Reporting group description |
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||||||
Date |
Amendment |
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09 Sep 2016 |
1) Change of the reference laboratory responsible for the histological review (Referent: Stefano Pileri, MD, Unità di Emolinfopatologia, Istituto Europeo di Oncologia IEO - Milano).
2) Clarification regarding the biopsy specimen for histological review (Inclusion criteria). The relapse biopsy was particularly recommended if the relapse occurred more than a year before complete remission. If harmful to the patient, it was possible to enroll if the tumor specimen or block from the first diagnosis was available.
3) Correction of typos concerning ancillary biological studies. All the references to the conduct of biological studies, which are not included in the protocol, have been removed.
4) Patient information sheet / Informed consent form / Privacy protection / Letter for the treating physician were modified with non-substantial corrections, modifications, additions and clarifications as requested by the local Ethics Committees in order to standardize the documentation for all sites.
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09 Sep 2016 |
5) Modifications to statistical considerations. The definition of toxicity considered unacceptable has been completed, in all the points in which it occurs, with the specification “grade 3-4 extra-haematological toxicity”, forgotten in the initial version. The correction is related, as obvious, to the fact that standard DHAP chemotherapy is almost always associated with pancytopenia that defines a grade 3 or 4 haematological toxicity which does not constitute an unexpected event that could compromise the costeffectiveness ratio of the therapeutic scheme. As already understood, but not specified in the initial text, all possible organ toxicities will be evaluated as unacceptable toxicities, including infectious complications following the expected pancytopenia. It has also been added a grade 3 or 4 toxicity level that identifies the unacceptability, since the lower grades are not relevant to imply a real clinical risk and also affect the stopping rule.
The preliminary stopping rule evaluation remains calculated on the percentages related to the first 29 patients. Taking into account the limited knowledge of the obinutuzumab-DHAP association, toxicity assessments at the end of chemotherapy with Ga101-DHAP of each patient have been specified (up to 1 month after the last cycle). Late assessments up to 6 months after the autotransplant were also planned, although these do not appear relevant to the stopping rule.
6) Increased study duration, extended to 88 months (52 months for enrollment and 36 months of follow up).
7) Withdrawal. It has been specified that it is possible to collect information on patient status for patients prematurely withdrawn from study participation.
8) Risks associated with GA101 Therapy. There have been added the guidelines to be followed in case a delayed administration of GA101 during the first cycle of therapy (day 8 and 15), in case toxicities occur. |
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09 Sep 2016 |
9) Investigator's Brochure Update. The risk/benefit profile was confirmed, therefore no modifications has been reported on the study documents.
10) Update of the participating centers. Five sites were closed and 4 sites were involved in the study.
11) Typos correction and other not substantial modification. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? Yes | |||||||
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Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||||||
| None reported | |||||||
