The OPAL Study: AVM0703 for Treatment of Lymphoid Malignancies

Phase 2 For Phase 2, one or more patient cohort(s) will receive repeat RP2D infusions in 21 day intervals until intolerance, unacceptable toxicity or disease progression, to determine the number of repeat infusions that are safe, effective and tolerable in this patient population. PK assessments will be made at sites participating in both Phase 1 and Phase 2 after each repeat infusion for the first 6 patients enrolled into each repeat dosing cohort. Full PK assessments will be made as per Phase 1 after the 1st (first) and 6th (sixth) repeat infusions, while for the second to fifth doses (2nd to 5th) PK assessments will be made pre-infusion, at end of infusion, 15 minutes and 48 hours after end of infusion. At least 6 patients will be enrolled in each RP2D repeat dosing cohort. The DSMC will monitor unacceptable toxicities during Phase 2 and halting/stopping criteria are outlined in Table 6. After 6 patients, who have had PK assessments, have reached intolerance, unacceptable toxicity, or disease progression, or they have received 6 infusions without intolerance, unacceptable toxicity, or disease progression, the Data Safety Monitoring Committee will review an integrated interim analysis of all available PK, PD, efficacy, safety and tolerability data and determine whether repeat dosing should continue or be limited to a certain number of infusions. Ongoing DSMC review will occur at least every 6 months. Based on integrated analysis, including dose-response and exposure-response, the DSMC will determine the optimal dose and dosing schedule for repeat dosing with AVM0703.

For Phase 2, RP2D cohorts will be included that do not require repeat 21 day interval dosing for patients who cannot comply with the visit schedule for repeat dosing. These patients can be retreated according to section 5.5.3.2.

An 18 mg/kg dose (expressed as dexamethasone phosphate) has been approved by the SRC for an RP2D. The 21 mg/kg dose-escalation cohort remains open for dose-escalation enrollment. For sites participating in both Phase 1 and Phase 2, patients will be enrolled into the 21 mg/kg dose-cohort unless i) no slot is available, ii) the patient cannot logistically comply with the PK blood draw requirements, iii) the cohort has been fully enrolled, or iv) the patient is enrolled into a Phase 2 repeat dosing RP2D cohort.

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.

The Phase 2 portion of the study will include patients with malignancies that are potentially 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.

For patients not enrolled into 21 day repeat dosing cohorts, 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.