An Open-Label, Phase 1/2 Study Evaluating AVM0703 in Patients With Lymphoid Malignancies (WWRD Study)

Description

Phase 1 The Phase 1 portion of the study will enroll patients into a 3+3 dose-escalation design to assess the dose-limiting toxicities (DLTs) and establish an Maximum tolerated dose (MTD)/Recommended Phase 2 does (RP2D). Up to 9 sequential AVM0703 dose cohorts are planned. In each cohort, 3 to 6 patients will be treated. Each patient in each cohort will be sequentially enrolled after 7 days of observation. Dose escalation will be allowed after 3 patients have completed the 21-day DLT assessment period with no reported DLTs or after 6 patients have completed the 21-day DLT assessment period with no more than 1 DLT.

The dose escalation will use the following rules for evaluating dose levels:

• If none of the first 3 evaluable patients in a cohort experience a DLT, that dose level will be deemed safe, and another 3 patients will be treated at the next higher dose level;
• If 1 of the first 3 patients in a cohort experiences a DLT, 3 more patients will be treated at the same dose level; If ≥2 of the 3 to 6 patients in any dose level experience a DLT, that dose level will be considered to have exceeded the MTD and dosing will stop at that level. If the previous dose level did not already have 6 patients treated with ≤1 DLT, enrollment and dosing will then resume in the previous dose level with additional patients up to a total of 6 patients. The highest dose level at which no more than 1 of 6 evaluable patients has experienced a DLT in the 21-day DLT assessment period will be considered the MTD for AVM0703; and
• If ≤1 patient experience(s) a DLT at the highest dose level tested, an MTD will not have been established, but sufficient data may be available to select an RP2D based on the overall safety profile.

Upon disease relapse, patients may be retreated at a dose previously shown to be safe.

Dose Escalation Plan Dose Cohort AVM0703 Dose (a) Cohort 1: 6 mg/kg Cohort 2: 9 mg/kg Cohort 3: 12 mg/kg Cohort 4: 18 mg/kg Cohort 5: 21 mg/kg

(a) Expressed as dexamethasone phosphate. For prophylaxis against dexamethasone-induced CNS side effects, hydrocortisone will be dosed orally for 5 days starting on the day of dexamethasone infusion. Hydrocortisone will be divided into 3 daily doses starting in the morning and spaced 6 to 8 hours apart using the following dosing schedule each day: for pediatric and adolescent patients at 5 mg/m2 (morning dose), 3 mg/m2 (mid day dose), and 2 mg/m2 dose (evening dose); and for adult patients at 10 mg/m2 (morning dose), 5 mg/m2 (mid-day dose), and 5 mg/m2 dose (evening dose), the last dose administered at hour of sleep.

• Prophylaxis for GI bleeding: Administer a proton pump inhibitor or H2 blocker starting at least 1 day prior to and for approximately 4 weeks after AVM0703 administration, as per institutional guidelines.
• Prophylaxis for TLS: All patients should be assessed for risk of TLS. Patients at high risk for TLS are defined as patients with ALC >25 × 109/L and/or who have a lymph node >10 cm. For patients at high risk of TLS, recommended prophylaxis is oral and IV hydration and anti hyperuricemic therapy (eg, allopurinol or rasburicase) starting at 2 days before AVM0703 administration.
• Prophylaxis for patients not deemed high risk for TLS will be at the discretion of the Investigator.
• Monitoring TLS: High-risk patients should have TLS labs (eg, potassium, phosphorus, calcium, uric acid, and creatinine) obtained predose, and 4 and 8 hours post-infusion of AVM0703 on Day 0.

Phase 2 To further assess safety and efficacy of AVM0703, disease-specific expansion cohorts will be opened in the Phase 2 portion of the study to obtain preliminary evidence of clinical activity. The Phase 2 portion of the study will include patients with malignancies that are deemed responsive to AVM0703, such as DLBCL (including DLBCL arising from follicular lymphoma and primary DLBCL of the CNS), high-grade B-cell lymphoma or Burkitt lymphoma, Chronic lymphocytic leukemia (CLL)/ SLL, T-cell lymphoma, or Acute lymphoblastic leukemia (ALL). Up to approximately 18 patients will be enrolled into each of the selected tumor types at the MTD/RP2D defined in the Phase 1 portion of the study.

Upon disease relapse, patients may be retreated at a dose previously shown to be safe.

If a patient must be given additional anticancer therapy before Day 28, disease assessment should be performed before they receive any other therapy. Patients who go on to receive additional anticancer therapy will be followed for survival at 3, 6, and 12 months post-infusion, and yearly thereafter until death, withdrawal of consent/assent, or study closure. Survival information can be obtained via public records, telephone calls, and/or medical records. Any subsequent anticancer therapy that the patients receive will also be collected.

For prophylaxis against dexamethasone-induced CNS side effects, hydrocortisone will be dosed orally for 5 days starting on the day of dexamethasone infusion. Hydrocortisone will be divided into 3 daily doses starting in the morning and spaced 6 to 8 hours apart using the following dosing schedule each day: for pediatric and adolescent patients at 5 mg/m2 (morning dose), 3 mg/m2 (mid day dose), and 2 mg/m2 dose (evening dose); and for adult patients at 10 mg/m2 (morning dose), 5 mg/m2 (mid-day dose), and 5 mg/m2 dose (evening dose), the last dose administered at hour of sleep.

• Prophylaxis for GI bleeding: Administer a proton pump inhibitor or H2 blocker starting at least 1 day prior to and for approximately 4 weeks after AVM0703 administration, as per institutional guidelines.
• Prophylaxis for TLS: All patients should be assessed for risk of TLS. Patients at high risk for TLS are defined as patients with ALC >25 × 109/L and/or who have a lymph node >10 cm. For patients at high risk of TLS, recommended prophylaxis is oral and IV hydration and anti hyperuricemic therapy (eg, allopurinol or rasburicase) starting at 2 days before AVM0703 administration.
• Prophylaxis for patients not deemed high risk for TLS will be at the discretion of the Investigator.
• Monitoring TLS: High-risk patients should have TLS labs (eg, potassium, phosphorus, calcium, uric acid, and creatinine) obtained predose, and 4 and 8 hours post-infusion of AVM0703 on Day 0.

Details