Lymphoma
Conditions
Keywords
DLCL, Nodular lymphoma, Mantle cell lymphoma, Syk kinase
Brief summary
Patients: B-cell lymphoma, refractory, diffuse, nodular, mantle, other Phase I : Two groups of 6 patients, escalating dose tolerability- 28 days Phase II: Three groups of 16 patients (nodular, diffuse large cell, mantle cell plus others). Oral bid dosing with highest tolerable dose until toxicity, progression, or withdrawal
Detailed description
This multicenter, open-label study of fostamatinib will take place in two phases. Phase I Two cohorts, of 6 patients each, will be sequentially assigned to receive 200 mg (Cohort 1) and 250 mg (Cohort 2) PO bid of R788. Patients will be enrolled at 250 mg bid in Cohort 2 only if \< 1/6 patients in Cohort 1 experience dose-limiting toxicity (DLT) during the initial 28-day treatment period. If 2 or more patients in Cohort 1 experience DLT during the initial 28-day treatment period, patients in Cohort 2 will receive 150 mg PO bid. Patients who do not experience DLT or disease progression may continue treatment at the assigned dose level until disease progression, toxicity or withdrawal. Patients who experience DLT may resume treatment at a lower dose level (dose will be decreased by 50 mg) when the toxicity grade has decreased to ≤ 1. Once all patients in Phase I have completed 28 days of treatment, the optimal dose of fostamatinib, based on safety and anti-tumor activity, will be determined. Phase II 48 additional patients, 3 groups of 16 patients each, will receive fostamatinib at the optimal biologic dose PO bid until tumor progression, limiting toxicity or withdrawal. Group 1 will consist of patients with diffuse large B-cell lymphoma (DLBCL), Group 2 will consist of patients with follicular lymphoma, and Group 3 will consist of patients with mantle cell lymphoma, mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphomas, small lymphocytic lymphomas (SLL), and chronic lymphocytic leukemia (CLL).
Interventions
DRUGfostamatinib
200 mg PO BID
Sponsors
Rigel Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. Patients must be \> 18 years old. 2. Patients must be willing and able to give written informed consent by signing an IRB-approved Informed Consent Form prior to admission to this study and must fully understand the requirements of the study and be willing to comply with all study visits and assessments. 3. Patients with relapsed/refractory B-cell malignancy, (DLBCL, follicular lymphoma, mantle cell lymphoma, MALT lymphoma, marginal zone lymphoma, CLL or SLL), who have failed at least one prior treatment regimen and for whom no standard therapy exists; patients who are intolerant of standard therapy or who are not candidates for available standard therapy may also be included. 4. Patients must have measurable disease. 5. Patients may be male or female. Men, if sexually active, must agree to use at least one medically acceptable form of birth control for the duration of the study and for 30 days thereafter. Sexually active women of childbearing potential must have a negative serum pregnancy test, and agree to use two independent methods of birth control for the duration of the study and for 30 days thereafter.
Exclusion criteria
1. Patients with T-cell lymphoma or primary CNS lymphoma 2. Patients with a history of malignancy other than lymphoma, except basal cell carcinoma of the skin and in situ cervical carcinoma, if \< 2 years since curative treatment 3. Chemotherapy within 4 weeks of Day 1 of treatment (6 weeks for mitomycin C and nitrosoureas) 4. Antibody therapy or lymphoma vaccine therapy within 6 weeks of Day 1 5. Radiotherapy within 2 weeks of Day 1, 4 weeks if to marrow-bearing sites (sternum, pelvis) 6. Any other investigational therapy within 4 weeks of Day 1 7. Significant gastrointestinal disease (Crohn's or ulcerative colitis) or major gastric or small bowel surgery 8. Difficulty swallowing or malabsorption 9. Patients with bone marrow impairment: Hgb \< 9.0 g/dL; ANC \< 1500/μL; platelets \< 75,000/μL 10. Patients with impairment of renal function: creatinine \> 2.0 g/dL 11. Patients with abnormal liver function: AST/ALT \> 3x ULN (up to 5x ULN with liver involvement); bilirubin \> 1.5 mg/dL 12. Patients who have been treated with a CYP3A4 inducer/inhibitor within 1 week prior to Day 1 or who are expected to require treatment with CYP3A4 inducer/inhibitor during the course of the study (Appendix IV) 13. Patients with Karnofsky performance status \< 60% (Appendix I) 14. Patients whose life expectancy is \< 3 months 15. Patients who are known to be HIV positive 16. Patients who have a history of any other significant medical or physical condition that might impair the patient's well being or preclude full participation in the study 17. Pregnant or nursing females 18. Patients receiving systemic or chronic inhaled steroids, with the exception of intermittent dexamethasone for the treatment of emesis or intermittent steroid inhalers for exacerbations of asthma
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate as Assessed According to theRevised Response Criteria for Malignant Lymphoma (Cheson 2007). | Serial tumor assessments were taken at baseline (within 28 days of the start of treatment), and re-evaluated at Day 57, and every 12 weeks thereafter or to confirm response . (Maximum duration of treatment 511 days, Maximum duration of follow-up 812 Days) | Proportion of patients with Complete Response (CR) or Partial Response (PR). Revised Response Criteria for Malignant Lymphoma categorises the response of the treatment of a patient's tumour to; CR: the disappearance of all evidence of disease; PR: ≥ 50% decrease in the sum of the perpendicular diameters (SPD) of the six largest dominant nodes plus no increase in the size of other nodes and no new sites of disease; Stable Disease (SD): less than a PR but not progressive disease; Relapsed Disease or PD: Any new lesion or increase by ≥ 50% of previously involved sites from nadir. Primary efficacy is based on Phase II patients only. |
| Clinical Benefit Rate as Assessed According to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). | Serial tumor assessments were taken at baseline (within 28 days of the start of treatment), and re-evaluated at Day 57, and every 12 weeks thereafter or to confirm response (Maximum duration of treatment 511 days, Maximum duration of follow-up 812 Days) | Proportion of patients with Complete Response (CR), Partial Response (PR), or Stable Disease (SD) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | Serial tumor assessments were taken at baseline (within 28 days of the start of treatment), and re-evaluated at Day 57, and every 12 weeks thereafter or to confirm response (Maximum duration of treatment 511 days, Maximum duration of follow-up 812 Days) | PFS: Time from date of first study drug administration to the date of progressive disease as assessed according to the Revised Response Criteria for Malignant Lymphoma(Cheson 2007) or the date of death due to any cause, whichever occurred first. |
| Overall Survival (OS) | Overall survival is measured from the time of first administration of study drug to death. (Maximum duration of treatment 511days, Maximum duration of follow-up 812 Days) | OS: Time from date of first study drug administration to the date of death. |
Countries
United States
Participant flow
Recruitment details
A total of 81 patients with lymphoid malignancy were enrolled from 22 March 2007 until 31 January 2008, of which 13 were in Phase I and 68 in Phase II. This study was conducted by 11 investigators at 11 sites in U.S. Primary efficacy analysis was based on Phase II patients so only results from Phase II are posted.
Pre-assignment details
There was screening period of up to 21 days, after which if all inclusion/exclusion criteria were met, patients were dosed with fostamatinib treatment for a treatment period of 8 weeks. Patients could then continue treatment until disease progression, toxicity or withdrawal from the study
Participants by arm
| Arm | Count |
|---|---|
| Phase II: DLBCL Patients with diffuse large B-cell lymphoma (DLBCL) in Phase II | 23 |
| Phase II: 250mg R788 BID Patients who received 250mg R788 orally twice daily (PO BID) in Phase II | 21 |
| Phase II: Other Lymphomas Patients with mantle cell lymphoma, mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphomas, small lymphocytic lymphomas and chronic lymphocytic leukemia (SLL/CLL) in Phase II | 24 |
| Phase I: 200mg R788 BID Patients who received 200mg R788 orally twice daily (PO BID) in Phase I | 6 |
| Phase I: 250mg R788 BID Patients who received 250mg R788 orally twice daily (PO BID) in Phase I | 7 |
| Total | 81 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Phase I (28 Days) | Adverse Event | 0 | 0 | 0 | 1 | 0 |
| Phase I (28 Days) | Lack of Efficacy | 0 | 0 | 0 | 0 | 3 |
| Phase II (8 Weeks) | Adverse Event | 0 | 1 | 1 | 0 | 0 |
| Phase II (8 Weeks) | Lack of Efficacy | 9 | 2 | 1 | 0 | 0 |
| Phase II (8 Weeks) | Lost to Follow-up | 1 | 0 | 0 | 0 | 0 |
| Phase II (8 Weeks) | Ongoing | 0 | 0 | 1 | 0 | 0 |
| Phase II (8 Weeks) | Physician Decision | 1 | 0 | 0 | 0 | 0 |
| Phase II (8 Weeks) | Withdrawal by Subject | 1 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Phase II: 250mg R788 BID | Phase II: Other Lymphomas | Phase I: 200mg R788 BID | Phase II: DLBCL | Phase I: 250mg R788 BID | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 59.0 Years FULL_RANGE 59 | 62.0 Years FULL_RANGE 62 | 78.5 Years | 63.0 Years FULL_RANGE 63 | 61 Years | 61.5 Years FULL_RANGE 61.5 |
| Race/Ethnicity, Customized Asian | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Black/African American | 0 Participants | 3 Participants | 0 Participants | 2 Participants | 1 Participants | 6 Participants |
| Race/Ethnicity, Customized Caucasian | 19 Participants | 21 Participants | 6 Participants | 20 Participants | 5 Participants | 71 Participants |
| Race/Ethnicity, Customized Other: Russian | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Female | 8 Participants | 7 Participants | 4 Participants | 5 Participants | 5 Participants | 29 Participants |
| Sex: Female, Male Male | 13 Participants | 17 Participants | 2 Participants | 18 Participants | 2 Participants | 52 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 22 / 23 | 21 / 21 | 24 / 24 | 6 / 6 | 6 / 7 |
| serious Total, serious adverse events | 14 / 23 | 7 / 21 | 10 / 24 | 6 / 6 | 3 / 7 |
Outcome results
Primary
Clinical Benefit Rate as Assessed According to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007).
Proportion of patients with Complete Response (CR), Partial Response (PR), or Stable Disease (SD)
Time frame: Serial tumor assessments were taken at baseline (within 28 days of the start of treatment), and re-evaluated at Day 57, and every 12 weeks thereafter or to confirm response (Maximum duration of treatment 511 days, Maximum duration of follow-up 812 Days)
Population: Intention to treat (ITT) population is defined as all patients who received at least one dose of fostamatinib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase II: DLBCL | Clinical Benefit Rate as Assessed According to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). | 9 Participants |
| Phase II: 250mg R788 BID | Clinical Benefit Rate as Assessed According to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). | 13 Participants |
| Phase II: Other Lymphomas | Clinical Benefit Rate as Assessed According to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). | 14 Participants |
| Phase 1: 200mg and 250mg R788 BID | Clinical Benefit Rate as Assessed According to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). | 9 Participants |
Primary
Overall Response Rate as Assessed According to theRevised Response Criteria for Malignant Lymphoma (Cheson 2007).
Proportion of patients with Complete Response (CR) or Partial Response (PR). Revised Response Criteria for Malignant Lymphoma categorises the response of the treatment of a patient's tumour to; CR: the disappearance of all evidence of disease; PR: ≥ 50% decrease in the sum of the perpendicular diameters (SPD) of the six largest dominant nodes plus no increase in the size of other nodes and no new sites of disease; Stable Disease (SD): less than a PR but not progressive disease; Relapsed Disease or PD: Any new lesion or increase by ≥ 50% of previously involved sites from nadir. Primary efficacy is based on Phase II patients only.
Time frame: Serial tumor assessments were taken at baseline (within 28 days of the start of treatment), and re-evaluated at Day 57, and every 12 weeks thereafter or to confirm response . (Maximum duration of treatment 511 days, Maximum duration of follow-up 812 Days)
Population: Intention to treat (ITT) population is defined as all patients who received at least one dose of fostamatinib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase II: DLBCL | Overall Response Rate as Assessed According to theRevised Response Criteria for Malignant Lymphoma (Cheson 2007). | 5 Participants |
| Phase II: 250mg R788 BID | Overall Response Rate as Assessed According to theRevised Response Criteria for Malignant Lymphoma (Cheson 2007). | 2 Participants |
| Phase II: Other Lymphomas | Overall Response Rate as Assessed According to theRevised Response Criteria for Malignant Lymphoma (Cheson 2007). | 7 Participants |
| Phase 1: 200mg and 250mg R788 BID | Overall Response Rate as Assessed According to theRevised Response Criteria for Malignant Lymphoma (Cheson 2007). | 1 Participants |
Secondary
Overall Survival (OS)
OS: Time from date of first study drug administration to the date of death.
Time frame: Overall survival is measured from the time of first administration of study drug to death. (Maximum duration of treatment 511days, Maximum duration of follow-up 812 Days)
Population: Phase II only as was not collected in Phase I. Intention to treat (ITT) population is defined as all patients who received at least one dose of fostamatinib.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase II: DLBCL | Overall Survival (OS) | 166.0 Days |
| Phase II: 250mg R788 BID | Overall Survival (OS) | NA Days |
| Phase II: Other Lymphomas | Overall Survival (OS) | NA Days |
Secondary
Progression Free Survival (PFS)
PFS: Time from date of first study drug administration to the date of progressive disease as assessed according to the Revised Response Criteria for Malignant Lymphoma(Cheson 2007) or the date of death due to any cause, whichever occurred first.
Time frame: Serial tumor assessments were taken at baseline (within 28 days of the start of treatment), and re-evaluated at Day 57, and every 12 weeks thereafter or to confirm response (Maximum duration of treatment 511 days, Maximum duration of follow-up 812 Days)
Population: Phase II only as was not collected in Phase I. Intention to treat (ITT) population is defined as all patients who received at least one dose of fostamatinib.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase II: DLBCL | Progression Free Survival (PFS) | 83.0 Days |
| Phase II: 250mg R788 BID | Progression Free Survival (PFS) | 141.0 Days |
| Phase II: Other Lymphomas | Progression Free Survival (PFS) | 126.0 Days |