A Phase 1/2 Study of ALX148 in Combination with Azacitidine in Patients with Higher Risk Myelodysplastic Syndrome (MDS) (ASPEN-02)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Alx Oncology Holdings Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

21 Sep 2022 → 11 Jun 2025

Decision date (initial)

2024-06-18

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

ALX Oncology Holdings Inc.

External identifiers

EU CT number

2024-513993-23-00

EudraCT number

2021-000705-25

ClinicalTrials.gov

NCT04417517

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Therapy, Safety, Efficacy, Pharmacokinetic

Phase 1: To evaluate the safety and tolerability of ALX148 administered in combination with AZA in adult patients with relapsed/refractory MDS or previously untreated higher risk MDS as defined by IPSS-R score >3.5; To identify the RP2D
of ALX148 in combination with AZA
Phase 2: To assess the effect of ALX148 administered at the RP2D determined in Phase 1 in combination with AZA versus AZA alone on the investigator-assessed complete response rate (CRR) per modified IWG 2006 criteria in adult patients with previously-untreated higher risk MDS (IPSS-R score >3.5)

Secondary objectives 8

1. Phase 1: Evaluate overall safety profile of ALX148 in combination with AZA;
2. Phase 1: Characterize safety profile of MTD or RP2D of ALX148 in combination with AZA;
3. Phase 1: Characterize single/multiple-dose pharmacokinetics (PK) of ALX148 in combination with AZA;
4. Phase 1: Evaluate immunogenicity of ALX148;
5. Phase 1: Document any evidence of antitumor activity;
6. Phase 2: Assess the effect of ALX148 administered at the RP2D determined in Phase 1 in combination with AZA versus AZA alone on the complete response rate (CRR) per modified IWG 2006 criteria as determined by independent central review in adult patients with previously-untreated higher risk MDS (IPSS-R score >3.5);
7. Phase 2: Assess secondary measures of efficacy for ALX148 administered in combination with AZA versus AZA alone;
8. Phase 2: Assess the safety and tolerability of ALX148 administered in combination with AZA versus AZA alone;

Conditions and MedDRA coding

Patients with higher risk myelodysplastic syndrome (MDS) who have not yet been treated for their disease

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Phase 1 dose escalation part: Adult patients with documented diagnosis of relapsed/refractory MDS or higher risk MDS (IPSS-R score >3.5) that is previously untreated. For patients with relapsed/refractory MDS, prior exposure to hypomethylating agents is allowed. Patients with previously untreated disease must have had no prior exposure to hypomethylating agents or cytotoxic chemotherapy (prior use of single agent lenalidomide for low or intermediate-1 risk MDS with deletion 5q abnormality is allowed) for the treatment of MDS and be appropriate candidates for single-agent AZA. Phase 1 dose expansion part and phase II: Adult patients with documented diagnosis of higher risk MDS (IPSS-R score >3.5) who have had no prior exposure to hypomethylating agents or cytotoxic chemotherapy (prior use of single agent lenalidomide for low or intermediate-1 risk MDS with deletion 5q abnormality is allowed) for the treatment of MDS, and are considered appropriate candidates for single-agent AZA.
2. Phase 1 dose expansion part and phase II: Bone marrow with <20% myeloblasts.
3. Adequate Renal Function with estimated creatinine clearance > or =30 mL/min as calculated using the method standard for the institution.
4. Adequate Liver Function, including: a. Total serum bilirubin < or =1.5 x ULN (< or =3.0 x ULN if the patient has documented Gilbert syndrome); b. Aspartate and alanine transaminase (AST and ALT) < or =3.0 x ULN; < or =5.0 x ULN if due to leukemic organ involvement; c. Alkaline phosphatase < or =2.5 x ULN; (< or =5.0 x ULN if bone or liver metastasis).
5. WBC < 20,000/microL. Administration of hydroxyurea for WBC control is permitted during the screening period up to and including treatment day -1 of the study (ie, one day prior to starting study treatment).
6. QTcF interval of < or =480 msec (Based upon mean value from triplicate ECGs).
7. Age > or = 18 years because MDS is extremely rare in the pediatric (<18 yrs) population.
8. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) must be 0, 1 or 2.
9. Resolved acute effects of any prior therapy to baseline severity or Grade < or =1 NCI CTCAE v.5.0 except for AEs not constituting a safety risk by Investigator judgment.
10. Serum pregnancy test (for females of childbearing potential) negative at screening.
11. Male and female patients of childbearing potential must agree to use a highly effective method of contraception throughout the study and for at least 120 days after the last dose of assigned treatment. A patient is of childbearing potential if, in the opinion of the Investigator, he/she is biologically capable of having children and is sexually active.
12. Evidence of a personally signed and dated informed consent document indicating that the patient (or legal representative) has been informed of all pertinent aspects of the study before any study-specific activity is performed.
13. Patients who are willing and able to comply with scheduled visits, treatment plans, laboratory, tests and other procedures.

Exclusion criteria 14

1. Patients with a history of autoimmune hemolytic anemia, autoimmune thrombocytopenia, or hemolytic transfusion reaction secondary to an acquired allo-antibody
2. Any of the following in the previous 6 months: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, NYHA Class II or greater congestive heart failure, uncontrolled hypertension, cerebrovascular accident, transient ischemic attack, deep venous thrombosis (except for thrombi considered device-associated and not clinically significant), arterial thrombosis, symptomatic pulmonary embolism, or any other significant thromboembolism. Any major surgery, within 28 days prior to enrollment.
3. Current active treatment in another interventional therapeutic clinical study.
4. Prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, prostate/breast/other cancer under control with hormone therapy alone, or other cancer from which the subject has been disease free for at least 2 years and felt to be at low risk for recurrence by the treating physician.
5. Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
6. Previous allogeneic hematopoietic stem cell transplant (allo-HSCT) for MDS or AML. If allo-HSCT was performed for another disease, patient must be at least a year post-HSCT, off all treatment for graft-versus-host disease (GVHD), and without any active GVHD.
7. Prior treatment with any anti-CD47 or anti-SIRPalpha agent.
8. Phase 1 dose escalation only: prior cytotoxic chemotherapy, CAR-T, or other cellular or experimental therapy within 4 weeks of starting study treatment. If any of these therapies (except hydroxyurea up to day -1 of study) was given within 4 weeks, patient may be included if at least 4 times the elimination half-life of the drug has passed Phase 1 dose expansion part and Phase 2: Prior treatment with any hypomethylating agents or cytotoxic chemotherapy for MDS (except hydroxyurea up to day -1 of study and lenalidomide for low or intermediate-1 risk MDS with deletion 5q abnormality).
9. Phase 1 dose expansion part and Phase 2: Patients with MPN/MDS overlap syndromes, including CMML.
10. Prior treatment with myeloid growth factors and erythropoiesis stimulating agents (ESAs) must be discontinued a minimum of 4-5 half-lives prior to initiation of study treatment.
11. Patients with intolerance to or who have had a severe allergic or anaphylactic reaction to antibodies or infused therapeutic proteins or patients who have had a severe allergic or anaphylactic reaction to any of the substances included in the study drug (including excipients).
12. Any experimental antibodies or live vaccines in the last 28 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist) are live attenuated vaccines and are not allowed.
13. Known active viral infections, including hepatitis B (HBV), hepatitis C (HCV), human immunodeficiency virus (HIV), acquired immunodeficiency syndrome (AIDS) related illness, or known active infection with SARS-CoV-2 (testing to be performed per local criteria).
14. Other severe acute or chronic medical or psychiatric condition, including uncontrolled systemic infection, recent (within the past year) or active suicidal ideation or behavior, or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient inappropriate for entry into this study. Please refer to section 4.2 of the protocol for exclusion criteria 15 and 16.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Phase 1, Dose escalation: First Cycle DLTs using CTCAE v5.0
2. Phase 1, Dose expansion: Adverse Events as characterized by type, frequency, severity (as graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v. 5.0), timing, seriousness, and relationship to study therapy
3. Phase 2 part of the study is complete response rate (CRR), assessed by investigator using modifed IWG 2006 response criteria for MDS, defined as a best response of CR, with the final analysis to be performed after the last patient has completed 6 cycles of treatment or is considered evaluable for response.

Secondary endpoints 8

1. Incidence of marrow CR, objective response rate (ORR), hematologic improvement (HI) in erythrocytes (E), platelets (P), and neutrophils (N), red blood cell (RBC) and platelet (PLT) transfusion independence, frequency and level of measurable residual disease (MRD)
2. Duration of response (DOR), event-free survival (EFS), progression-free survival (PFS), overall survival (OS), time to progression (TTP).
3. Percentage of patients able to proceed to allogeneic hematopoietic stem cell transplant (allo-HSCT)
4. Changes in global health status/quality of life (GHS/QoL) status based on patient reported outcome (PRO) assessment (Phase 2 only)
5. Phase 1 dose escalation and Phase 2: Adverse Events as characterized by type, frequency, severity (as graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v. 5.0), timing, seriousness, and relationship to study therapy;
6. Laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE v. 5.0) and timing
7. Pharmacokinetic parameters of ALX148 such as Cmax, Tmax, AUC, CL, and t1/2 as data permit
8. Immunogenicity; Human serum ADA (anti-ALX148 antibody) samples will be analyzed for the presence or absence of anti-ALX148 antibodies

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Alx Oncology Holdings Inc.

Sponsor organisation

Alx Oncology Holdings Inc.

Address

323 Allerton Avenue

City

South San Francisco

Postcode

94080-4816

Country

United States

Scientific contact point

Organisation

Alx Oncology Holdings Inc.

Contact name

Sr. VP of Clinical Development

Public contact point

Organisation

Alx Oncology Holdings Inc.

Contact name

Sr. VP of Clinical Development

Third parties 7

Locations

1 EU/EEA country · 4 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 11 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications