Theresa Deisher PhD at AVM Biotechnology discusses The WWRD Study: AVM0703 for Treatment of Leukemia or Lymphoma
Description in detail:
Phase 1 Patients will be included in the Phase 1 segment of the study in a 3 + 3 dose-escalation design to determine dose-limiting toxicity (DLT) and set the Maximum Tolerated Dose (MTD)/Recommended Phase 2 (RP2D). Up to 9 cohorts of the sequential dose AVM0703 are expected. 3 to 6 patients are enrolled in each cohort. After 7 days of evaluation-patient in each cohort is sequentially enrolled. After 3 patients have completed the 21-day DLT evaluation period with no confirmed DLTs, or after 6 patients have completed the 21-day DLT evaluation period with no more than 1 DLT, dose escalation will be permitted.
The dose escalation will use the following principles for the dose levels evaluation:
If no DLT is encountered in any of the first 3 evaluable patients in a cohort, the dose level will be considered safe and another 3 will be treated at the next higher dose level;
If DLT is encountered by 1 of the first 3 patients in a cohort, 3 more patients will be treated at the same dose level; if DLT is encountered by 2 of the 3 to 6 patients at any dose level, that dose level will be deemed to have exceeded MTD and dosing will cease at that level. If the previous dose level did not already have 6 patients treated with .. 1 DLT, registration and dosage will restart with additional patients up to a total of 6 patients in the previous dose level. The MTD for AVM0703 will be considered the highest dose level at which no more than 1 out of 6 evaluable patients have encountered a DLT in the 21-day DLT evaluation period; and
If a DLT has been tested at the highest dose level, an MTD will not be identified, but there may be enough data available to pick an RP2D based on the overall safety profile.
Upon relapse of the disease, patients may be removed at a dosage that was previously established safe.
Dose Escalation Strategy Cohort dose AVM0703 Dose (a) 1 6 mg / kg 2 9 mg / kg 3 12 mg / kg 4 15 mg / kg 6 21 mg / kg
(a) Expressed as the phosphate of dexamethasone. Hydrocortisone will be dosed orally for 5 days beginning on the day of the dexamethasone infusion for prophylaxis against the CNS side effects caused by dexamethasone. Hydrocortisone will be divided into 3 regular doses beginning in the morning and 6 to 8 hours apart, using the following regular dosing schedule: 5 mg / m2 (morning dose) for pediatric and adolescent patients, 3 mg / m2 (mid-day dose) and 2 mg / m2 (evening dose) for pediatric and adolescent patients; 10 mg / m2 (morning dose) for adult patients, 5 mg / m2 (mid-day dose) and 5 mg / m2 (evening dose) for pediatric and adolescent patients, 10 mg / m2 (morning dose) for adults, 5 mg / m2
GI bleeding prophylaxis: Administer a proton pump inhibitor or H2 blocker beginning at least 1 day before and for about 4 weeks after administration of AVM0703, as per the institutional guidelines.
TLS prophylaxis: All patients are to be tested for TLS risk. High-risk patients with TLS are classified as ALC > 25 > 109 / L and/or lymph node > 10 cm patients. Recommended prophylaxis for patients at high risk of TLS is oral and IV hydration and anti-hyperuricemic treatment (e.g., allopurinol or rasburicase) beginning at 2 days before AVM0703.
Prophylaxis shall be at the Investigator’s discretion for patients not found to be at high risk for TLS.
TLS monitoring: high-risk patients should have AVM0703 predose labs (e.g., potassium, phosphorus , calcium, uric acid, and creatinine) and 4 and 8 hours after infusion on Day 0.
Phase 2 In the Phase 2 section of the study, disease-specific expansion cohorts will be opened to obtain preliminary evidence of clinical activity for further evaluation of the safety and effectiveness of AVM0703. Patients with malignancies known to be susceptible to AVM0703, such as DLBCL (including DLBCL resulting from follicular lymphoma and primary CNS DLBCL), high-grade B-cell lymphoma or Burkitt lymphoma, Chronic Lymphocytic Leukemia (CLL)/SLL, T-cell lymphoma, or Acute Lymphoblastic Leukemia (ALL), will be included in the Phase 2 portion of the research. Up to approximately 18 patients will be included in the MTD / RP2D identified in the Phase 1 portion of the study for each of the selected tumor types.
Upon relapse of the disease, patients may be removed at a dosage that was previously established safe.
If additional anticancer therapy needs to be given to a patient before Day 28, disease assessment should be done before any other therapy is obtained. For survival at 3, 6 , and 12 months after infusion, and annually thereafter until death, withdrawal of consent / assent, or study termination, patients who continue to undergo additional anticancer therapy will be monitored. It is possible to obtain survival information through public records, phone calls, and/or medical records. It will also collect any future anticancer treatment the patients obtain.
Hydrocortisone will be dosed orally for 5 days beginning on the day of the dexamethasone infusion for prophylaxis against the CNS side effects caused by dexamethasone. Hydrocortisone will be divided into 3 regular doses beginning in the morning and 6 to 8 hours apart, using the following regular dosing schedule: 5 mg / m2 (morning dose) for pediatric and adolescent patients, 3 mg / m2 (mid-day dose) and 2 mg / m2 (evening dose) for pediatric and adolescent patients; 10 mg / m2 (morning dose) for adult patients, 5 mg / m2 (mid-day dose) and 5 mg / m2 (evening dose) for pediatric and adolescent patients, 10 mg / m2 (morning dose) for adults, 5 mg / m2
GI bleeding prophylaxis: Administer a proton pump inhibitor or H2 blocker beginning at least 1 day before and for about 4 weeks after administration of AVM0703, as per the institutional guidelines.
TLS prophylaxis: All patients are to be tested for TLS risk. High-risk patients with TLS are classified as ALC > 25 > 109 / L and/or lymph node > 10 cm patients. Recommended prophylaxis for patients at high risk of TLS is oral and IV hydration and anti-hyperuricemic treatment (e.g., allopurinol or rasburicase) beginning at 2 days before AVM0703.
Prophylaxis shall be at the Investigator’s discretion for patients not found to be at high risk for TLS.
TLS monitoring: high-risk patients should have AVM0703 predose labs (e.g., potassium, phosphorus , calcium, uric acid, and creatinine) and 4 and 8 hours after infusion on Day 0.