FIL_GAEL: GA101-miniCHOP Regimen for the Treatment of Elderly Unfit Patients With Diffuse Large B-cell Non-Hodgkin's Lymphoma

• Sponsor: Fondazione Italiana Linfomi ONLUS (Other)
• Overall Status: Terminated
• CT.gov ID: NCT02495454
• Collaborator: (none)
• Enrollment: 34
• Locations: 16
• Arm: 1
• Actual Duration (Months): 18.9
• Patients Per Site: 2.1
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

GA101-miniCHOP regimen for the treatment of elderly unfit patients with diffuse large B-cell non-Hodgkin's lymphoma.

Condition or Disease	Intervention/Treatment	Phase
CD20 Positive Diffuse Large B-cell Lymphoma; Elderly Unfit Patients	Drug: Ga101	Phase 2

Detailed Description

Considering that the treatment of elderly unfit patients with DLBCL cannot be based on a full course of R-CHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisone), and that using a less intense R-miniCHOP (an attenuated version of the standard R-CHOP: Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisone) combination an acceptable cure rate can be achieved this study is designed to try to improve the cure rate in unfit patients with DLBCL (Diffuse Large B Cell Lymphoma) by adopting the R-miniCHOP scheme substituting Rituximab with the more active GA101 monoclonal antibody. The study hypothesis is that a higher activity of the treatment can be achieved without modifying the cytotoxic part of the treatment but using a more active immunotherapy. Differently from the previous experience with R-miniCHOP eligible patient are not only identified using anagraphic criteria but adopting CGA (Comprehensive Geriatric Assessment) as part of initial assessment and considering as eligible unfit patients.

Study Design

• Study Type: Interventional
• Actual Enrollment: 34 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: GA101-miniCHOP Regimen for the Treatment of Elderly Unfit Patients With Diffuse Large B-cell Non-Hodgkin's Lymphoma A Phase II Study of the Fondazione Italiana Linfomi (FIL)
• Actual Study Start Date: Aug 25, 2015
• Actual Primary Completion Date: Mar 22, 2017
• Actual Study Completion Date: Mar 22, 2017

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Ga101-miniCHOP 6 courses of GA101-miniCHOP regimen and 2 additional infusions of GA101, every 21 days (for a total of 6 courses of miniCHOP and 10 infusions of GA101). GA101-miniCHOP regimen: Cycle 1 GA101: 1000 mg day 1, day 8 and day 15, iv Cyclophosphamide: 400 mg/mq, day 1, iv Doxorubicin: 25 mg/mq, day 1, iv Vincristine: 1 mg, day 1, iv Prednisone: 40 mg/mq, days 1-5, os Cycles 2-6 GA101: 1000 mg day 1, iv Cyclophosphamide: 400 mg/mq, day 1, iv Doxorubicin: 25 mg/mq, day 1, iv Vincristine: 1 mg, day 1, iv Prednisone: 40 mg/mq, days 1-5, os Two additional infusions of GA101: 1000 mg day 1, iv, every 21 days.

Drug: Ga101; Other Names: Obinutuzumab

Outcome Measures

Primary Outcome Measures

1. Complete Response Rate (CRR). Based a Central Independent Review Committee Considering Use the Conventional CT Scan Images. [Up to 36 months.]

   Complete Response Rate after 10 infusions of GA101 and 6 cycles of miniCHOP. Complete Remission (CR): Complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy, normalization of biochemistry abnormalities. If the bone marrow was involved by lymphoma before treatment, the infiltrate must be cleared on repeat bone marrow aspirate and biopsy of the same site. Partial disease (PR): >= 50% decrease in node diameter of the six largest dominant nodes or nodal masses and no new sites of disease; Stable disease (SD): is defined as less than a PR but is not progressive disease. Progession disease (PD): >50% increase diameter of node from nadir of any previously identified abnormal node nonresponders, and/or appearance of any new lesion.

Secondary Outcome Measures

1. Adverse Events (AEs) [Up to 36 months]

   Rate of Adverse Events. Although was not defined a formal threshold, in this section we reported the summary of frequencies of maximum CTCAE observed in patients. Each patient was counted only once within the AE terms during the therapy. If, during the therapy the patient experiences more than one AE, only the AE with the greatest intensity was included in the summary.

2. Partial Response Rate (PRR) [Up to 36 months]

   Partial Response Rate (PRR): patients in Partial Response after induction therapy. Frequency of PRR already reported in the table of principal end-point.

3. ORR (Overall Response Rate) [Up to 36 months]

   ORR (Overall Response Rate): sum of patiens with Complete or Partial response after the induction therapy.

4. OS (Overall Survival) [Up to 36 months]

   OS (Overall Survival): defined as the time from the date of treatment start into the study until the date of death irrespective of cause. Patients who have not died at the time of end of the whole study, and patients who are lost to follow up, will be censored at the date of the last contact.

5. PFS (Progression Free Survival) [Up to 36 months]

   PFS (Progression Free Survival): defined as the time from entry into the study until lymphoma relapse/ progression or death as a result of any cause. Responding patients, patients who are lost to follow up, who withdrawal the consent or drop-out due to adverse event will be censored at their last assessment date. Patients died due to tumor will be considered in progression. Patients died for any other cause will be censored to the death date.

6. Activities of Daily Living (ADL) [Up to 36 months]

   Change in Activities of daily living score. The score ranging from 0 (bad performance) to 6 (good performance)

7. Instrumental Activities of Daily Living (IADL) [Up to 36 months]

   Change in Instrumental Activities of Daily Living score. The score ranging from 0 (bad performance) to 8 (good performance).

8. Cumulative Illness Rating Scale (CIRS) [Up to 36 months]

   Change in Cumulative Illness Rating Scale. The grading of comorbidity ranging from 0 (absent) to 4 (severe).

9. Questionnaire for Quality of Life (EORTC QLQ C30) [Up to 36 months]

   Change in quality of life (QoL)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 65 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Histologically proven CD20 positive Diffuse Large B-cell Lymphoma and Follicular grade III B lymphoma, according to WHO (World Health Organization) classification (local pathologist)

2. Age ≥ 65 years

3. No previous treatment

4. CGA assessment (Comprehensive Geriatric Assessment) performed before starting treatment

5. Unfit patients defined as follows:

Age > 80 years with Fit profile, i.e. ADL (Activity of Daily Living) =6 residual functions IADL (Instrumental Activity of Daily Living) =8 residual functions CIRS (Cumulative Illness Rating Scale): no comorbidity of grade 3-4 and <5 of grade 2 or Age < 80 with Unfit profile, i.e ADL(Activity of Daily Living) > 5 residual functions IADL (Instrumental Activity of Daily Living) > 6 residual functions CIRS (Cumulative Illness Rating Scale): no comorbidity of grade 3-4 and 5-8 co-morbidities of grade 2

1. Ann Arbor Stage I with bulky, II-IV

2. At least one bi-dimensionally measurable lesion defined as > 1.5 cm in its largest dimension on CT scan

3. ECOG (Eastern Cooperative Oncology Group) performance status of 0, 1, or 2

4. Adequate hematologic function (unless caused by bone marrow infiltrate), defined as follows:

Hemoglobin ≥ 10 g/dL Absolute neutrophil count ≥ 1.5 x 109/L Platelet count ≥ 100 x 109/L

1. LVEF (Left Ventricular Ejection Fraction) >50%

2. Ability and willingness to comply with the study protocol procedure

3. Life expectancy > 6 months

4. Accessibility of patient for treatment and follow up

5. Written informed consent

Exclusion Criteria:

1. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies or known sensitivity or allergy to murine products

2. Contraindication to any of the individual components of CHOP (Cyclophosphamide, Doxorubicin, Vincristine, Prednisone), including prior receipt of anthracyclines

3. History of other malignancies within 5 years prior to study entry except for adequately treated carcinoma in situ of the cervix or basal or squamous cell skin cancer

4. Stage I without bulky

5. Patients with transformed lymphoma

6. Prior therapy for DLBCL (Diffuse Large B Cell Lymphoma), with the exception of nodal biopsy or local irradiation

7. Previous exposure to cytotoxic agents

8. Suspect or clinical evidence of CNS (Central Nervous System) involvement by lymphoma

9. HBsAg (Hepatitis B surface antigen), HCV (Hepatitis C Virus) or HIV (Human Immunodeficiency Virus) positivity; isolated HBcAb (Hepatitis B surface antibody) positivity is accepted only with concomitant treatment with Lamivudine

10. AST /ALT (Aspartate Aminotransferase/Alanine Aminotransferase)> twice upper the normal range; bilirubin > twice upper the normal range; serum creatinine > 2.5 mg /dl (unless these abnormalities were related to the lymphoma)

11. Evidence of any severe active acute or chronic infection

12. Concurrent co-morbid medical condition which might exclude administration of full dose chemotherapy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	A.O. Spedali Civili	Brescia	BS	Italy	25100
2	AUSL di Ravenna	Ravenna	RA	Italy	48100
3	Asmn-Irccs	Reggio Emilia	RE	Italy	43123
4	Ematologia 1U - AO Città della Salute e della Scienza	Torino	TO	Italy	10126
5	A.O. S. Maria di Terni	Terni	TR	Italy	05100
6	A.O. SS. Antonio e Biagio e C. Arrigo	Alessandria		Italy	15121
7	A.O. Universitaria Ospedali Riuniti - Ospedale Umberto I Di Ancona	Ancona		Italy	60126
8	A.O. Ospedale Degli Infermi	Biella		Italy	13900
9	Area Vasta Romagna e IRST	Meldola (FC)		Italy
10	IRCCS, Istituto Nazionale dei Tumori	Milano		Italy
11	A.O. Universitaria Policlinico Di Modena	Modena		Italy	41124
12	SCDU Ematologia - Università del Piemonte Orientale	Novara		Italy	28100
13	Irccs Istituto Oncologico Veneto (Iov)	Padova		Italy	35128
14	Oncoematologia e TMO Dopartimento Oncologia La Maddalena	Palermo		Italy
15	Ausl Di Rimini	Rimini		Italy	47924
16	Ematologia - OSPEDALE DI CIRCOLO E FONDAZIONE MACCHI	Varese		Italy	21100

Sponsors and Collaborators

• Fondazione Italiana Linfomi ONLUS

Investigators

• Principal Investigator: Francesco Merli, MD, Ematologia - IRCCS Arcispedale Santa Maria Nuova

Study Documents (Full-Text)

• Study Protocol - Sep 29, 2014
• Statistical Analysis Plan - Apr 30, 2020

More Information

Publications

None provided.

• Responsible Party: Fondazione Italiana Linfomi ONLUS
• ClinicalTrials.gov Identifier: NCT02495454
• Other Study ID Numbers: FIL_GAEL; 2014-005697-10
• First Posted: Jul 13, 2015
• Last Update Posted: Nov 5, 2020
• Last Verified: Aug 1, 2020

• Additional relevant MeSH terms: Lymphoma; Lymphoma, Non-Hodgkin; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Obinutuzumab

Study Results

Participant Flow

Pre-assignment Detail	One case excluded for violation of inclusion criteria (transformed lymphoma)

Arm/Group Title	Single Arm
Arm/Group Description	6 courses of GA101-miniCHOP regimen and 2 additional infusions of GA101, every 21 days (for a total of 6 courses of miniCHOP and 10 infusions of GA101) miniCHOP: an attenuated version of the standard CHOP, Cyclophosphamide, Doxorubicin, Vincristine, Prednisone
Period Title: Overall Study
STARTED	34
COMPLETED	33
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Single Arm
Arm/Group Description	6 courses of GA101-miniCHOP regimen and 2 additional infusions of GA101, every 21 days (for a total of 6 courses of miniCHOP and 10 infusions of GA101)
Overall Participants	33
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	0 0%
>=65 years	33 100%
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	82
Sex: Female, Male (Count of Participants)
Female	15 45.5%
Male	18 54.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	33 100%
Not Hispanic or Latino	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
Italy	33 100%
Hemoglobin (g/dL) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [g/dL]	12.9
Stage (Count of Participants)
II	6 18.2%
III	11 33.3%
IV	16 48.5%
Bone Marrow Involvement (Count of Participants)
Negative	27 81.8%
Positive	6 18.2%
Symptoms (Count of Participants)
Absence of symptoms	27 81.8%
Presence of symptoms	6 18.2%
ECOG PS (Eastern Cooperative Oncology Group Performance Status) (Count of Participants)
0	12 36.4%
1	19 57.6%
2-3	2 6.1%
LDH (lactate dehydrogenase) (Count of Participants)
<= Upper Limit	10 30.3%
> Upper Limit	23 69.7%
International Prognostic Index (Count of Participants)
0-1	4 12.1%
2	8 24.2%
3/5	21 63.6%
Comprehensive Geriatric Assessment (Count of Participants)
UNFIT	28 84.8%
FRAIL	5 15.2%

Outcome Measures

1. Primary Outcome

Title	Complete Response Rate (CRR). Based a Central Independent Review Committee Considering Use the Conventional CT Scan Images.
Description	Complete Response Rate after 10 infusions of GA101 and 6 cycles of miniCHOP. Complete Remission (CR): Complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy, normalization of biochemistry abnormalities. If the bone marrow was involved by lymphoma before treatment, the infiltrate must be cleared on repeat bone marrow aspirate and biopsy of the same site. Partial disease (PR): >= 50% decrease in node diameter of the six largest dominant nodes or nodal masses and no new sites of disease; Stable disease (SD): is defined as less than a PR but is not progressive disease. Progession disease (PD): >50% increase diameter of node from nadir of any previously identified abnormal node nonresponders, and/or appearance of any new lesion.
Time Frame	Up to 36 months.

Outcome Measure Data

Analysis Population Description

Patients who received at last 1 cycle of treatment

Arm/Group Title	Single Arm
Arm/Group Description	6 courses of GA101-miniCHOP regimen and 2 additional infusions of GA101, every 21 days (for a total of 6 courses of miniCHOP and 10 infusions of GA101)
Measure Participants	33
Complete Response	14 42.4%
Partial Response	8 24.2%
Stable Disease	2 6.1%
Progression Disease	8 24.2%
Not Assessed	1 3%

2. Secondary Outcome

Title	Adverse Events (AEs)
Description	Rate of Adverse Events. Although was not defined a formal threshold, in this section we reported the summary of frequencies of maximum CTCAE observed in patients. Each patient was counted only once within the AE terms during the therapy. If, during the therapy the patient experiences more than one AE, only the AE with the greatest intensity was included in the summary.
Time Frame	Up to 36 months

Outcome Measure Data

Analysis Population Description

Patients who received at least 1 cycle of treatment.

Arm/Group Title	Single Arm
Arm/Group Description	6 courses of GA101-miniCHOP regimen and 2 additional infusions of GA101, every 21 days (for a total of 6 courses of miniCHOP and 10 infusions of GA101)
Measure Participants	33
CTCAE Grade 0	5 15.2%
CTCAE grade 1-2	11 33.3%
CTCAE grade >2	17 51.5%

3. Secondary Outcome

Title	Partial Response Rate (PRR)
Description	Partial Response Rate (PRR): patients in Partial Response after induction therapy. Frequency of PRR already reported in the table of principal end-point.
Time Frame	Up to 36 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Single Arm
Arm/Group Description	6 courses of GA101-miniCHOP regimen and 2 additional infusions of GA101, every 21 days (for a total of 6 courses of miniCHOP and 10 infusions of GA101) miniCHOP: an attenuated version of the standard CHOP, Cyclophosphamide, Doxorubicin, Vincristine, Prednisone
Measure Participants	33
Partial Remission	8 24.2%
Not in partial remission	25 75.8%

4. Secondary Outcome

Title	ORR (Overall Response Rate)
Description	ORR (Overall Response Rate): sum of patiens with Complete or Partial response after the induction therapy.
Time Frame	Up to 36 months

Outcome Measure Data

Analysis Population Description

Patients who received at leat 1 cycle of treatment

Arm/Group Title	Single Arm
Arm/Group Description	6 courses of GA101-miniCHOP regimen and 2 additional infusions of GA101, every 21 days (for a total of 6 courses of miniCHOP and 10 infusions of GA101)
Measure Participants	33
ORR	22 66.7%
Less than ORR	11 33.3%

5. Secondary Outcome

Title	OS (Overall Survival)
Description	OS (Overall Survival): defined as the time from the date of treatment start into the study until the date of death irrespective of cause. Patients who have not died at the time of end of the whole study, and patients who are lost to follow up, will be censored at the date of the last contact.
Time Frame	Up to 36 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Single Arm
Arm/Group Description	6 courses of GA101-miniCHOP regimen and 2 additional infusions of GA101, every 21 days (for a total of 6 courses of miniCHOP and 10 infusions of GA101)
Measure Participants	33
Mean (95% Confidence Interval) [Probability at 24 months]	0.69

6. Secondary Outcome

Title	PFS (Progression Free Survival)
Description	PFS (Progression Free Survival): defined as the time from entry into the study until lymphoma relapse/ progression or death as a result of any cause. Responding patients, patients who are lost to follow up, who withdrawal the consent or drop-out due to adverse event will be censored at their last assessment date. Patients died due to tumor will be considered in progression. Patients died for any other cause will be censored to the death date.
Time Frame	Up to 36 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Single Arm
Arm/Group Description	6 courses of GA101-miniCHOP regimen and 2 additional infusions of GA101, every 21 days (for a total of 6 courses of miniCHOP and 10 infusions of GA101)
Measure Participants	33
Mean (95% Confidence Interval) [Probability at 24 months]	0.53

7. Secondary Outcome

Title	Activities of Daily Living (ADL)
Description	Change in Activities of daily living score. The score ranging from 0 (bad performance) to 6 (good performance)
Time Frame	Up to 36 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Secondary Outcome

Title	Instrumental Activities of Daily Living (IADL)
Description	Change in Instrumental Activities of Daily Living score. The score ranging from 0 (bad performance) to 8 (good performance).
Time Frame	Up to 36 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Secondary Outcome

Title	Cumulative Illness Rating Scale (CIRS)
Description	Change in Cumulative Illness Rating Scale. The grading of comorbidity ranging from 0 (absent) to 4 (severe).
Time Frame	Up to 36 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

10. Secondary Outcome

Title	Questionnaire for Quality of Life (EORTC QLQ C30)
Description	Change in quality of life (QoL)
Time Frame	Up to 36 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	50 months
Arm/Group Title	Single Arm
Arm/Group Description	6 courses of GA101-miniCHOP regimen and 2 additional infusions of GA101, every 21 days (for a total of 6 courses of miniCHOP and 10 infusions of GA101). NOTE: One SAE (atrial fibrillation) was recorded in patient excluded from analysis (not eligible for transformed lymphoma), exit before starting the 1st cycle of treatment.
All Cause Mortality
	Single Arm
	Affected / at Risk (%)	# Events
Total	11/33 (33.3%)
Serious Adverse Events
	Single Arm
	Affected / at Risk (%)	# Events
Total	6/33 (18.2%)
Cardiac disorders
Congestive heart failure	2/33 (6.1%)	6
BCPO-Heart failure	1/33 (3%)	6
Atrial fibrillation	1/33 (3%)	6
Gastrointestinal disorders
Nausea	1/33 (3%)	6
General disorders
Femur fracture	2/33 (6.1%)	6
Infections and infestations
-sepsis	4/33 (12.1%)	6
Musculoskeletal and connective tissue disorders
Lumbar pain, vertebral collapse	1/33 (3%)	6
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer	3/33 (9.1%)	6
Non small cell lung cancer	3/33 (9.1%)	6
Other (Not Including Serious) Adverse Events
	Single Arm
	Affected / at Risk (%)	# Events
Total	30/33 (90.9%)
Blood and lymphatic system disorders
Anemia	6/33 (18.2%)	30
Leukopenia	4/33 (12.1%)	30
Neutropenia	15/33 (45.5%)	30
Thrombocytopenia	11/33 (33.3%)	30
Cardiac disorders
Cardiac disorders	5/33 (15.2%)	30
Gastrointestinal disorders
Gastrointestinal disorders	12/33 (36.4%)	30
General disorders
General disorders	6/33 (18.2%)	30
Other	8/33 (24.2%)	30
Hepatobiliary disorders
Hepatobiliary disorders	2/33 (6.1%)	30
Infections and infestations
Infections	7/33 (21.2%)	30
Injury, poisoning and procedural complications
Injury	2/33 (6.1%)	30
Investigations
Investigations	3/33 (9.1%)	30
Metabolism and nutrition disorders
Metabolism	8/33 (24.2%)	30
Musculoskeletal and connective tissue disorders
Musculoskeletal	8/33 (24.2%)	30
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasm	2/33 (6.1%)	30
Nervous system disorders
Nervous system	7/33 (21.2%)	30
Renal and urinary disorders
Renal	2/33 (6.1%)	30
Respiratory, thoracic and mediastinal disorders
Respiratory	5/33 (15.2%)	30
Vascular disorders
Vascular	1/33 (3%)	30

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Sponsor, in accordance with art.5 of DM, minist. decree (Feb8,2013), guarantees the publication of the results of the study without any constraints and ensuring all the participating centres a proportional visibility to the actual participation. The single centre will be able to publish partial data of patients treated at the centre after the publication of the global results, or 24 months after the last patient's enrolment date, regardless of which centre the last patient was recruited at.