Follicular Lymphoma
Conditions
Keywords
Idelalisib, Obinutuzumab, Relapsed/Refractory Follicular Lymphoma
Brief summary
Single arm, prospective, multi-centric, phase II study. Patients with histologically confirmed follicular lymphoma, in need of a systemic approach and failing (i.e. with refractory disease \[no response or response lasting less than 6 months at any previous line of treatment\] or with a proven disease relapse) at least 2 previous lines of treatment, including any antibody directed against the CD20 antigen-containing chemotherapy, will undergo a combined chemo-free treatment with obinutuzumab and idelalisib.
Detailed description
Single arm, prospective, multi-centric, phase II study. Patients with histologically confirmed follicular lymphoma, in need of a systemic approach and failing (i.e. with refractory disease \[no response or response lasting less than 6 months at any previous line of treatment\] or with a proven disease relapse) at least 2 previous lines of treatment, including any antibody directed against the CD20 antigen-containing chemotherapy, will undergo a combined chemo-free treatment with obinutuzumab and idelalisib. Obinutuzumab will be administered intravenously at a flat dose of 1000 mg on day 1, 8, 15 of the first cycle, then repeated on day 1 of each subsequent cycle, for 6 cycles (each cycle is completed in 28 days). Idelalisib will be given concomitantly with obinutuzumab and on a daily 150 mg bid schedule. For patients achieving at least a partial response at the end of induction, a maintenance phase with obinutuzumab is scheduled (on day 1 every two months for two years or until progression or unacceptable toxicity, whichever comes first) If one of the two drugs has to be permanently discontinued due to any cause, patient may continue treatment with the other agent if it is judged to be a clinical benefit. Patients with at least a stable disease will enter the follow-up phase and will be followed with repeated CT scans every six months for two years or until death/progression occurs (whichever comes firsts). Patients with progressive disease, whenever progression is documented, will enter a survival follow up period of two years after PD was documented. These patients are however considered evaluable for OS.
Interventions
DRUGIdelalisib
Idelalisib Plus Obinutuzumab In Patients With Relapsed/Refractory Follicular Lymphoma
DRUGObinutuzumab
Idelalisib Plus Obinutuzumab In Patients With Relapsed/Refractory Follicular Lymphoma
Sponsors
Fondazione Italiana Linfomi - ETS
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Single arm: Regimen: GAUDEALIS q28 days * Obinutuzumab Dose: 1000 mg IV Day 1, 8, 15 (1st cycle) * Obinutuzumab Dose: 1000 mg IV Day 1 (2nd cycle onward) * Idelalisib Dose: 150 mg BID oral Daily (24 weeks) Obinutuzumab will be administered intravenously at a flat dose of 1000 mg on day 1, 8, 15, of the first cycle, then repeated on day 1 of each subsequent cycle, for 6 cycles in total (each cycle is completed in 28 days). Idelalisib will be given concomitantly with obinutuzumab on a daily 150 mg bid schedule orally and continuously (24 weeks).
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
Relapsed or refractory, histologically confirmed CD20-positive follicular non-Hodgkin's lymphoma, grade 1, 2 or 3a according to WHO 2017 classification. * Age 18 ≥ years * At least 2 prior systemic therapies for follicular lymphoma including both any antibody directed against the CD20 antigen and a chemotherapy combination. * Treatment indications, with the presence of at least one of the following: * bulky disease (nodal or extranodal mass - except spleen -more than 7 cm in its greater diameter or involvement of at least 3 nodal or extranodal sites, each with a diameter equal to or greater than 3 cm); * at least one B-symptom (fever \> 38°C of unclear etiology, night sweats, weight loss greater than 10% of body weight in the prior 6 months); * symptomatic splenomegaly; * compression syndrome (i.e. of orbits, ureters, gastrointestinal tract, biliary tract); * lymphoma-related cytopenias (hemoglobin \< 10 g/dL and/or platelets \< 100.000/mmc and/or neutrophils \< 1.500/mmc); * pleural or peritoneal serous effusions; * lactate dehydrogenase elevation. * Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2. * Adequate hematological function, unless abnormalities due to underlying disease, within 28 days prior to signing informed consent, defined as follows: neutrophils \> 1.500/mmc, platelets \> 75.000/mmc, hemoglobin \> 8,0 g/dL with transfusion independence. * Capacity and willingness to adhere to study visit schedule and specific protocol procedures. * Willingness to sign a written informed consent. * Compliance with effective contraception without interruption, from 28 days before treatment start up (i.e., during the screening phase) to 18 months after treatment discontinuation, agreeing not to donate the semen during treatment and for 18 months after discontinuation (if the patient is male), or to undergo ongoing pregnancy test during the course of the study (if the patient is female). * Patients must agree to undergo JPJ prophylaxis throughout the treatment period and 2-6 months thereafter (before consulting with Medical Monitor).
Exclusion criteria
Grade 3b follicular non-Hodgkin's lymphoma or evidence of transformation to high-grade non-Hodgkin's lymphoma. * Central nervous system or leptomeningeal involvement by lymphoma. * Major surgery (excluding any lymph node biopsy) within 28 days prior to signing informed consent. * Seropositivity for HBV or evidence of active infection (HBsAg positivity, or HBsAg negativity with positive anti-HBs/anti-HBc and detectable viral DNA load); if viral load is negative or undetectable, the patient is eligible, provided their HBsAg negativity. * Positive viral HCV RNA * Seropositivity for HIV, regardless of viral load. * Known history of drug induced liver injury, chronic active hepatitis C (HCV), chronic active hepatitis B (HBV), alcoholic liver disease, non-alcoholic steatohepatitis, primary biliary cirrhosis, on-going extra-hepatic obstruction caused by cholelithiasis, cirrhosis of the liver or portal hypertension * Known history of drug induced pneumonitis * On-going inflammatory bowel disease * On-going alcohol or drug addiction * Life expectancy lower than 6 months. * Prior history of malignancies, other than follicular lymphoma, unless the patient has been free for at least 10 years (exceptions: localized non-melanoma skin cancer ad carcinoma in situ of the cervix). * Any of the following laboratory abnormalities: liver enzymes (AST/SGOT and/or ALT/SGPT) \> 2.5-fold the upper limit of normal (except of liver involvement by lymphoma); total bilirubin \> 1.5 mg/dL (except for patients with known Gilbert's disease or biliary tree compression by lymphoma masses); creatinine clearance \< 30 mL/min. * Uncontrolled intercurrent illness. * Known hypersensitivity or allergy to murine products or to any of the medicaments under investigation. * Pregnancy or breastfeeding, or unwillingness to comply with adequate contraception. * Any serious medical condition, laboratory abnormality or psychiatric illness that would prevent the patient from signing the informed consent or which may place the patient at unacceptable risk if participating in the study. * Any evidence of ongoing bacterial, viral and fungal infection.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Primary Endpoint - Overall Response Rate (ORR) | Six months after the start of treatment | Investigator's assessed Overall response rate at the end of induction phase of patients treated with a chemo-free combination with obinutuzumab and idelalisib. Overall response rate is defined as the proportion of patients with at least a partial response according with 2014 Lugano criteria. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Secondary Endpoints 1 - Overall Survival (OS) Rate | Up to 24 months from the start of treatment | Overall survival (OS) rate, measured from the date of starting therapy to the date of death from any cause. Patients alive and patients who are lost to follow up at the time of the final analysis will be censored at the date of the last contact. |
| Secondary Endpoints 2 - Progression-free Survival (PFS) Rate | Up to 24 months from the start of treatment | Progression-free survival (PFS) rate: measured from the date of starting 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 censored at their last assessment date. Patients who will have no tumor assessment after the start of therapy due to interruption of both drugs will be considered failures at the date of treatment interruption in the PFS analysis |
| Secondary Endpoints 3 - Patients' Withdrawal Rate | Up to 24 months from the start of treatment | patients' withdrawal rate, incidence and nature of any severe adverse events hospitalization rate throughout the study, and patients' compliance to oral treatment, incidence of any adverse events occurring during and right after treatment |
Other
| Measure | Time frame | Description |
|---|---|---|
| Safety Monitoring | Six months from start of treatment | In order to monitor the safety of the treatment in small cohorts of patients, the Bayesian approach of Thall, et al. for monitoring toxicity will be used. We have planned the monitoring of toxicity to ensure that the proportion of patients with non-hematological toxicity defined as any non-hematological toxicity of grade 3 or higher after 3 and 6 cycles of induction was not higher than an acceptable level of 25%. The prior probability of toxicity (25%) is modeled by a beta distribution \[Beta (0.5,1.5)\]. |
Countries
Italy
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Idelalisib Plus Obinutuzumab Single arm: Regimen: GAUDEALIS q28 days
* Obinutuzumab Dose: 1000 mg IV Day 1, 8, 15 (1st cycle)
* Obinutuzumab Dose: 1000 mg IV Day 1 (2nd cycle onward)
* Idelalisib Dose: 150 mg BID oral Daily (24 weeks)
Idelalisib: Idelalisib Plus Obinutuzumab In Patients With Relapsed/Refractory Follicular Lymphoma
Obinutuzumab: Idelalisib Plus Obinutuzumab In Patients With Relapsed/Refractory Follicular Lymphoma | 5 |
| Total | 5 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Lack of Efficacy | 2 |
| Overall Study | Physician Decision | 1 |
Baseline characteristics
| Characteristic | Idelalisib Plus Obinutuzumab |
|---|---|
| Age, Continuous | 69 years |
| Ann Arbor Stage Stage I-II | 0 units on a scale |
| Ann Arbor Stage Stage III-IV | 5 units on a scale |
| ECOG Performance Status ECOG 0-1 | 5 units on a scale |
| ECOG Performance Status ECOG >1 | 0 units on a scale |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 5 |
| other Total, other adverse events | 4 / 5 |
| serious Total, serious adverse events | 2 / 5 |
Outcome results
Primary
Primary Endpoint - Overall Response Rate (ORR)
Investigator's assessed Overall response rate at the end of induction phase of patients treated with a chemo-free combination with obinutuzumab and idelalisib. Overall response rate is defined as the proportion of patients with at least a partial response according with 2014 Lugano criteria.
Time frame: Six months after the start of treatment
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Idelalisib Plus Obinutuzumab | Primary Endpoint - Overall Response Rate (ORR) | ORR (CR+PR) | 3 Participants |
| Idelalisib Plus Obinutuzumab | Primary Endpoint - Overall Response Rate (ORR) | SD/PD | 2 Participants |
Secondary
Secondary Endpoints 1 - Overall Survival (OS) Rate
Overall survival (OS) rate, measured from the date of starting therapy to the date of death from any cause. Patients alive and patients who are lost to follow up at the time of the final analysis will be censored at the date of the last contact.
Time frame: Up to 24 months from the start of treatment
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Idelalisib Plus Obinutuzumab | Secondary Endpoints 1 - Overall Survival (OS) Rate | Alive when stopped the study | 4 Participants |
| Idelalisib Plus Obinutuzumab | Secondary Endpoints 1 - Overall Survival (OS) Rate | Death | 1 Participants |
Secondary
Secondary Endpoints 2 - Progression-free Survival (PFS) Rate
Progression-free survival (PFS) rate: measured from the date of starting 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 censored at their last assessment date. Patients who will have no tumor assessment after the start of therapy due to interruption of both drugs will be considered failures at the date of treatment interruption in the PFS analysis
Time frame: Up to 24 months from the start of treatment
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Idelalisib Plus Obinutuzumab | Secondary Endpoints 2 - Progression-free Survival (PFS) Rate | Progression or death any cause when stop the study | 3 Participants |
| Idelalisib Plus Obinutuzumab | Secondary Endpoints 2 - Progression-free Survival (PFS) Rate | No events when stop the study | 2 Participants |
Secondary
Secondary Endpoints 3 - Patients' Withdrawal Rate
patients' withdrawal rate, incidence and nature of any severe adverse events hospitalization rate throughout the study, and patients' compliance to oral treatment, incidence of any adverse events occurring during and right after treatment
Time frame: Up to 24 months from the start of treatment
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Idelalisib Plus Obinutuzumab | Secondary Endpoints 3 - Patients' Withdrawal Rate | Early withdrawal along induction | 4 Participants |
| Idelalisib Plus Obinutuzumab | Secondary Endpoints 3 - Patients' Withdrawal Rate | Not wthdrawed in induction | 1 Participants |
Other Pre-specified
Safety Monitoring
In order to monitor the safety of the treatment in small cohorts of patients, the Bayesian approach of Thall, et al. for monitoring toxicity will be used. We have planned the monitoring of toxicity to ensure that the proportion of patients with non-hematological toxicity defined as any non-hematological toxicity of grade 3 or higher after 3 and 6 cycles of induction was not higher than an acceptable level of 25%. The prior probability of toxicity (25%) is modeled by a beta distribution \[Beta (0.5,1.5)\].
Time frame: Six months from start of treatment
Population: Safety monitoring analysis
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Idelalisib Plus Obinutuzumab | Safety Monitoring | No relevant toxicity | 2 Participants |
| Idelalisib Plus Obinutuzumab | Safety Monitoring | Relevant toxicity | 3 Participants |