The OPAL Study: AVM0703 for Treatment of Lymphoid Malignancies (OPAL)

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ClinicalTrials.gov Identifier: NCT04329728

Recruitment Status : Recruiting

First Posted : April 1, 2020

Last Update Posted : November 17, 2022

See Contacts and Locations

View this study on Beta.ClinicalTrials.gov

Sponsor:

Collaborator:

Medpace, Inc.

Information provided by (Responsible Party):

AVM Biotechnology Inc

Study Description

Brief 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.

Condition or disease	Intervention/treatment	Phase
Lymphoid Malignancies	Drug: AVM0703	Phase 1 Phase 2

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Detailed 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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	144 participants
Allocation:	Non-Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	An Open Label, Phase 1/2 Study Evaluating AVM0703 in Lymphoid Malignancies (OPAL Study)
Actual Study Start Date :	November 6, 2020
Estimated Primary Completion Date :	April 1, 2023
Estimated Study Completion Date :	June 1, 2023

Resource links provided by the National Library of Medicine

Genetic and Rare Diseases Information Center resources: Lymphosarcoma B-cell Lymphoma Diffuse Large B-Cell Lymphoma Follicular Lymphoma Acute Lymphoblastic Leukemia Mantle Cell Lymphoma Lymphoblastic Lymphoma Acute Graft Versus Host Disease Acute Leukemia of Ambiguous Lineage Chronic Lymphocytic Leukemia Chronic Graft Versus Host Disease Leukemia, T-cell, Chronic

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
Experimental: DLBCL and high-grade B-cell lymphoma Diffuse Large Cell B-Lymphoma High-grade B-cell Lymphoma	Drug: AVM0703 Intravenous infusion over ~1 hours Other Name: Supra-Pharmacologic Dexamethasone Phosphate
Experimental: MCL (Chronic Lymphoid Leukemia) Chronic Lymphoid Leukemia	Drug: AVM0703 Intravenous infusion over ~1 hours Other Name: Supra-Pharmacologic Dexamethasone Phosphate
Experimental: Primary Mediastinal Large B-cell lymphoma Primary mediastinal large B-cell lymphoma	Drug: AVM0703 Intravenous infusion over ~1 hours Other Name: Supra-Pharmacologic Dexamethasone Phosphate
Experimental: Burkitt or Burkitt-like lymphoma/leukemia Burkitt or Burkitt-like lymphoma/leukemia	Drug: AVM0703 Intravenous infusion over ~1 hours Other Name: Supra-Pharmacologic Dexamethasone Phosphate
Experimental: CLL/SLL Chronic Lymphocytic Leukemia Small Lymphocytic Lymphoma	Drug: AVM0703 Intravenous infusion over ~1 hours Other Name: Supra-Pharmacologic Dexamethasone Phosphate
Experimental: B- or T-ALL B-lymphoblastic leukemia/lymphoma, T-lymphoblastic leukemia/lymphoma, acute leukemia/lymphoma, acute leukemias of ambiguous lineage, or natural killer (NK) cell lymphoblastic leukemia/lymphoma	Drug: AVM0703 Intravenous infusion over ~1 hours Other Name: Supra-Pharmacologic Dexamethasone Phosphate

Outcome Measures

Primary Outcome Measures :

Phase 1: incidence of Adverse events [ Time Frame: Year One ]
The primary endpoint for the Phase 1 portion of the study is the incidence of Adverse events (AEs), including DLTs.

Secondary Outcome Measures :

Phase 2: ORR [ Time Frame: Year Two ]
ORR (CR plus partial response [PR]) at 28 days post infusion

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:	12 Years to 95 Years (Child, Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

1. 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:
  1. R/R after autologous HCT; or
  2. R/R after CAR T therapy; or
  3. 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
  4. R/R after ≥2 lines of therapy including anti-20 antibody. Patients must have failed or are intolerant or ineligible for polatuzamab vedotin;
- MCL:
  1. R/R after autologous HCT; or
  2. Ineligible for autologous HCT due to persistent disease, co-morbidity, or social issues (eg, lack of insurance, lack of caregiver, etc); or
  3. 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:
  
  a. 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:
  
  a. R/R after ≥1 line of therapy including methotrexate (unless intolerant to methotrexate);
- Burkitt or Burkitt-like lymphoma/leukemia:
  1. R/R after autologous or allogeneic HCT; or
  2. 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:
  1. R/R after autologous or allogeneic HCT; or
  2. Ineligible for autologous or allogeneic HCT due to persistent disease, co-morbidity, or social issues (eg, lack of insurance, lack of caregiver, etc); or
  3. R/R after ≥2 lines of therapy including at least 1 of the following: a BTK inhibitor, ventoclax, idelalisib, or duvelisib;
- ALL:
  1. R/R after autologous or allogeneic HCT; or
  2. Ineligible for allogeneic HCT due to persistent disease, co-morbidity, or social issues (eg, lack of insurance, lack of caregiver, etc); or
  3. 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:
1. 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.

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04329728

Contacts

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Contact: Vladimir Radosevic, MD	513 579 9911 ext 18360	V.Radosevic@Medpace.com
Contact: Theresa A Deisher, PhD	206 851 3942	tdeisher@avmbiotech.com

Locations

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United States, California
City of Hope	Recruiting
Duarte, California, United States, 91010
Contact: Elizabeth Budde, MD 626-218-2405 ebudde@coh.org
Contact: Ricardo Ortega ricortega@coh.org
Principal Investigator: Elizabeth Budde
Los Angeles Cancer Network	Recruiting
Los Angeles, California, United States, 90017
Contact: Lasika Seneviratne 213-977-1214 lasika.seneviratne@lahomg.com
Contact: Elizabeth Tica 213-977-1214 elizabeth.tica@lahomg.com
Principal Investigator: Lasika Seneviratne
UCLA Medical Center of Hematology/Oncology	Recruiting
Los Angeles, California, United States, 90095
Contact: Gary J. Schiller, MD 310-825-3513 gschiller@mednet.ucla.edu
Contact: Bruck Habtemariam 310-794-0242 bhabtemariam@mednet.ucla.edu
Principal Investigator: Gary J Schiller
United States, Kentucky
Norton Cancer Institute	Recruiting
Louisville, Kentucky, United States, 40207
Contact: Don Stevens, MD 502-899-3366 don.stevens@nortonhealthcare.org
Contact: Dana Haycraft 502-899-3366 ext 19287 Dana.Haycraft@nortonhealthcare.org
Principal Investigator: Don Stevens, MD
United States, Nebraska
Oncology Hematology West P.C. dba Nebraska Cancer Specialists	Recruiting
Omaha, Nebraska, United States, 68124
Contact: Stefano Tarantolo 402-334-4773 starantolo@nebraskacancer.com
Contact: Josh Settlemire 531-329-3651 jsettlemire@nebraskacancer.com
Principal Investigator: Stefano Tarantolo
United States, Tennessee
Baptist Clinical Research Institute	Recruiting
Memphis, Tennessee, United States, 38120
Contact: Salil Goorha 901-226-1485 salil.goorha@bmg.md
Contact: Lauren Wooten lauren.wooten@bmhcc.org
Principal Investigator: Salil Goorha
United States, Texas
University of Texas(UT) Southwestern-Children's Medical Center	Recruiting
Dallas, Texas, United States, 75235
Contact: Tamra Slone, MD 214-648-3896 tamra.slone@utsouthwestern.edu
Contact: Teresa Banda teresa.banda@childrens.com
Principal Investigator: Slone Tamra

Sponsors and Collaborators

AVM Biotechnology Inc

Medpace, Inc.

Investigators

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Principal Investigator:	Nicholas Short, MD	MD Anderson
Principal Investigator:	Elizabeth Budde, MD	City of Hope Medical Center
Principal Investigator:	Gary Schiller, MD	University of California, Los Angeles
Principal Investigator:	Farrukh T Awan, MD	U Texas SouthWestern

More Information

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Responsible Party:	AVM Biotechnology Inc
ClinicalTrials.gov Identifier:	NCT04329728
Other Study ID Numbers:	AVM0703-001
First Posted:	April 1, 2020 Key Record Dates
Last Update Posted:	November 17, 2022
Last Verified:	September 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

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Studies a U.S. FDA-regulated Drug Product:	Yes
Studies a U.S. FDA-regulated Device Product:	No

Keywords provided by AVM Biotechnology Inc:


Diffuse large B-cell lymphoma (DLBCL) B-cell lymphoma Mantle cell lymphoma (MCL) Primary mediastinal large B-cell Lymphoma Primary DLBCL of the central nervous system (CNS) Burkitt or Burkitt-like lymphoma/leukemia Chronic lymphocytic leukemia (CLL)	Small lymphocytic leukemia (SLL) B-cell leukemia/lymphoma T-cell leukemia/lymphoma Acute leukemias of ambiguous lineage Natural Killer (NK) cell lymphoblastic leukemia/lymphoma Advanced or Aggressive lymphoma/lymphoproliferative disease Follicular Lymphoma

Additional relevant MeSH terms:

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Neoplasms Dexamethasone Dexamethasone 21-phosphate Anti-Inflammatory Agents Antiemetics Autonomic Agents Peripheral Nervous System Agents	Physiological Effects of Drugs Gastrointestinal Agents Glucocorticoids Hormones Hormones, Hormone Substitutes, and Hormone Antagonists Antineoplastic Agents, Hormonal Antineoplastic Agents

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