The WWRD Study: AVM0703 for Treatment of Leukemia or Lymphoma

  • STATUS
    Recruiting
  • End date
    Jun 24, 2023
  • participants needed
    144
  • sponsor
    AVM Biotechnology LLC
Updated on 24 September 2021

Summary

This is an open-label, Phase 1/2 study designed to characterize the safety, tolerability, Pharmacokinetics(PK), and preliminary antitumor activity of AVM0703 administered as a single intravenous (IV) infusion to patients with lymphoid malignancies.

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: 15 mg/kg Cohort 5: 18 mg/kg Cohort 6: 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
Condition Lymphoid Malignancies
Treatment Supra-Pharmacologic Dexamethasone sodium phosphate, AVM0703
Clinical Study IdentifierNCT04329728
SponsorAVM Biotechnology LLC
Last Modified on24 September 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

\. Age 12 years and weight >40 kg; 2. Histologically confirmed diagnosis per 2016 World Health Organization (WHO) classification of lymphoid neoplasms160 and per the 2016 WHO classification of acute leukemia161 of the following indications
DLBCL, including arising from follicular lymphoma
High-grade B-cell lymphoma
MCL
Primary mediastinal large B-cell lymphoma
Primary DLBCL of the CNS
Burkitt or Burkitt-like lymphoma/leukemia
CLL/SLL; or
B-lymphoblastic leukemia/lymphoma, T-lymphoblastic leukemia/lymphoma, acute leukemia/lymphoma, acute leukemias of ambiguous lineage, or NK cell lymphoblastic leukemia/lymphoma; 3. Patients must have R/R disease with prior therapies defined below
DLBCL and high-grade B-cell lymphoma
R/R after autologous HCT; or
R/R after CAR T therapy; or
Ineligible for autologous HCT or CAR T therapy due to persistent disease, co-morbidity, or social issues (eg, lack of insurance, lack of caregiver, etc); or
R/R after 2 lines of therapy including anti-20 antibody. Patients must have failed or are intolerant or ineligible for polatuzamab vedotin
MCL
R/R after autologous HCT; or
Ineligible for autologous HCT due to persistent disease, co-morbidity, or social issues (eg, lack of insurance, lack of caregiver, etc); or
R/R after 2 lines of therapy including at least 1 of the following: a BTK inhibitor, bortezomib, or lenalidomide
Primary mediastinal large B-cell lymphoma
R/R after 1 line of therapy; AVM Biotechnology, LLC. Clinical Study Protocol AVM0703-001 Confidential & Proprietary Page 47 of 105 Version 1.0, 20 February 2020
Primary DLBCL of the CNS
R/R after 1 line of therapy including methotrexate (unless intolerant to methotrexate)
Burkitt or Burkitt-like lymphoma/leukemia
R/R after autologous or allogeneic HCT; or
Ineligible for autologous or allogeneic HCT due to persistent disease, co-morbidity, or social issues (eg, lack of insurance, lack of caregiver, etc)
CLL/SLL
R/R after autologous or allogeneic HCT; or
Ineligible for autologous or allogeneic HCT due to persistent disease, co-morbidity, or social issues (eg, lack of insurance, lack of caregiver, etc); or
R/R after 2 lines of therapy including at least 1 of the following: a BTK inhibitor, ventoclax, idelalisib, or duvelisib
ALL
R/R after autologous or allogeneic HCT; or
Ineligible for allogeneic HCT due to persistent disease, co-morbidity, or social issues (eg, lack of insurance, lack of caregiver, etc); or
R/R according to the following disease-specific specifications
B-cell lymphoblastic leukemia/lymphoma: 2 lines of therapy including approved CAR T cell therapies, inotuzumab, ozogamicin, or blinatumomab; or
T-cell lymphoblastic leukemia/lymphoma: Patients must have failed nelarabine; or
NK cell lymphoblastic leukemia/lymphoma: R/R after 1 line of therapy; 4. Lansky (12 to 15 years of age) (Appendix G) or Karnofsky (16 years of age) (Appendix H) performance status 50; 5. Screening laboratory values that meet all of the following criteria
Absolute neutrophil count 0.5 109/L
Platelet count >50 109/L
Hemoglobin 8.0 g/dL
Aspartate aminotransferase or alanine aminotransferase 2.5 ULN, unless due to the disease
Total bilirubin 1.5 ULN (if secondary to Gilbert's syndrome, 3 ULN is permitted), unless due to the disease; and
Serum creatinine 1.5 ULN or glomerular filtration rate 50 mL/min (calculated from a 24-hour urine collection); 6. Minimum level of pulmonary reserve defined as <Grade 2 dyspnea and pulse oximetry 92% on room air; 7. Females of childbearing potential must have a negative serum pregnancy test at screening. Females of childbearing potential and nonsterile males must agree to use medically effective methods of contraception from the time of informed consent/assent through 1 month after study drug infusion, which must, at a minimum, include a barrier method; and 8. The ability to understand and willingness to sign a written informed consent form (ICF) and the ability to adhere to the study schedule and prohibitions. Patients under the age of 18 years (or other age as defined by regional law or regulation) must be willing and able to provide written assent and have a parent(s) or guardian(s) willing and able to provide written, signed informed consent after the nature of the study has been explained and prior to performance of any study-related procedure

Exclusion Criteria

Patients who meet any of the following criteria will be excluded from participation in the study
History of another malignancy, except for the following
Adequately treated local basal cell or squamous cell carcinoma of the skin
Adequately treated carcinoma in situ without evidence of disease
Adequately treated papillary, noninvasive bladder cancer; or
Other cancer that has been in complete remission for 2 years. Patients with low-grade prostate cancer, on active surveillance, and not expected to clinically progress over 2 years are allowed; 2. Significant cardiovascular disease (eg, myocardial infarction, arterial thromboembolism, cerebrovascular thromboembolism) within 3 months prior to the start of AVM0703 administration, angina requiring therapy, symptomatic peripheral vascular disease, New York Heart Association Class III or IV congestive heart failure, left ventricular ejection fraction <30%, left ventricular fractional shortening <20%, or uncontrolled Grade 3 hypertension (diastolic blood pressure [DBP] 100 mmHg or systolic blood pressure [SBP] 150 mmHg) despite antihypertensive therapy for patients 18 years of age, or uncontrolled stage 2 hypertension (DBP 90 mmHg or SBP 140 mmHg) despite antihypertensive therapy for patients 12 years of age; 3. Significant screening electrocardiogram (ECG) abnormalities, including unstable cardiac arrhythmia requiring medication, atrial fibrillation/flutter, left bundle-branch block, second-degree atrioventricular (AV) block type 2, third-degree AV block, Grade 2 bradycardia, or heart rate corrected QT interval using Fridericia's formula average of triplicate ECGs >450 msec; 4. Known gastric or duodenal ulcer; 5. Uncontrolled type 1 or type 2 diabetes; 6. Known hypersensitivity or allergy to the study drug or any of its excipients; 7. Untreated ongoing bacterial, fungal, or viral infection (including upper respiratory tract infections) at the start of AVM0703 administration, including the following
Positive hepatitis B surface antigen and/or hepatitis B core antibody test plus a positive hepatitis B polymerase chain reaction (PCR) assay. Patients with a negative PCR assay are permitted with appropriate antiviral prophylaxis
Positive hepatitis C virus antibody (HCV Ab) test. Patients with a positive HCV Ab test are eligible if they are negative for hepatitis C virus by PCR
Positive human immunodeficiency virus (HIV) antibody test with detectable HIV load by PCR, or the patient is not able to tolerate antiretroviral therapy; or
Positive testing for tuberculosis during screening; 8. Received live vaccination within 8 weeks of screening; 9. Pregnant or breastfeeding; 10. Concurrent participation in another therapeutic clinical study; or 11. Manic-depressive disorder, schizophrenia, or a history of severe depression or substance abuse
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