A phase II study evaluating the efficacy and safety of IMetelstat in Patients with HR myElodysplastic SyndromeS or AML failing HMA-based therapy.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Gcp-Service International West GmbH

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15], Diseases [C] - Neoplasms [C04]

Decision date (initial)

2023-01-27

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

Geron Corporation

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To assess the efficacy of Imetelstat for the treatment of AML and MDS patients failing or being refractory to first line hypomethylating agent (HMA)-based treatment

Secondary objectives 6

1. • Toxicity as measured by NCI CTCAE v5.0
2. • Overall survival
3. • Progression-free-survival
4. • Duration of response
5. • Best overall response
6. • Quality of Life (EORTC QLQ-C30)

Conditions and MedDRA coding

AML and MDS patients failing or being refractory to hypomethylating agent (HMA)-based treatment

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 16

1. Signed written informed consent
2. Male and female ≥ 18 years at the first screening
3. Must be able to adhere to the study visit schedule and other protocol requirements
4. Initial diagnosis of AML or MDS according to WHO 2016 classification
5. At least one cytopenia (ANC < 1800/μL or platelet count < 100,000/μL or hemoglobin < 10 g/dL)
6. a. Failure to achieve complete or partial response or hematological improvement observed after at least six azacitidine monotherapy or four decitabine monotherapy based 4-week treatment cycles administered during the past two years OR b. Failure to achieve complete or partial response or hematological improvement observed after at least two 4-week treatment cycles with azacitidine plus venetoclax or with decitabine plus venetoclax during the past two years OR c. Relapse after initial complete or partial response or hematological improvement observed after at least six (azacitidine) or four (decitabine) based 4-week treatment cycles administered during the past two years OR d. Relapse after initial complete or partial response or hematological improvement observed after at least two 4-week treatment cycles with azacitidine plus venetoclax or with decitabine plus venetoclax during the past two years OR e. Intolerance to treatment with HMA-based therapy during the past two years
7. Not eligible for allogeneic stem cell transplantation
8. ≥ 5% bone marrow blasts at screening
9. Off all other treatments for AML/MDS for at least 14 days; G-CSF and erythropoietin are allowed before and during the study as clinically indicated
10. ECOG performance status of 0-2
11. Biochemical laboratory test values must be within the following limits: a. AST, ALT and ALP ≤2.5 times the upper limit of normal (x ULN) b. Serum creatinine ≤2.0 x ULN c. Total bilirubin ≤3 x ULN and direct bilirubin ≤2 x ULN (unless due to Gilbert’s syndrome, ineffective erythropoiesis due to MDS, or hemolysis due to RBC transfusion)
12. Availability of blood counts and transfusion events for previous 16 weeks
13. Women of childbearing potential and practicing a highly effective method of birth control according to the Clinical Trial Facilitation Coordination Group Recommendation (Version 1.1, 2020)28: - combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: o oral o intravaginal o transdermal - progestogen-only hormonal contraception associated with inhibition of ovulation: o oral o injectable o implantable - intrauterine device (IUD) - intrauterine hormone-releasing system ( IUS) - bilateral tubal occlusion - vasectomised partner - sexual abstinence For females, these restrictions apply for 3 months after the end of dosing. Note: If the childbearing potential changes after start of the study (e.g., woman who is not heterosexually active becomes active, premenarchal woman experiences menarche) a woman must begin a highly effective method of birth control, as described above
14. A woman of childbearing potential must have a negative serum (ẞ-human chorionic gonadotropin [ẞ-hCG] pregnancy test at screening and agree to be tested (serum or urine) on day 1 of every cycle and at EOT
15. A man who is sexually active with a woman of childbearing potential and has not had a vasectomy must agree to use a barrier method of birth control eg, either condom with spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository, and all men must also not donate sperm during the study. For males, these restrictions apply for 3 months after the end of dosing
16. France-specific inclusion criterion: Subjects participating at French sites must be covered by the French public welfare system.

Exclusion criteria 13

1. Chemotherapy within the 14 days prior to the first dose of imetelstat being administered (other than hydroxyurea)
2. Subject has known allergies, hypersensitivity, or intolerance to imetelstat or its excipients (refer to the IB)
3. Subject has received an experimental or investigational drug or used an invasive investigational medical device within 30 days prior to day 1 of C1
4. Prior treatment with imetelstat
5. Prior history of intensive chemotherapy or hematopoietic stem cell transplant
6. Major surgery within 4 weeks prior to day 1 of C1 (excluding the placement of vascular access and other minor surgical procedures)
7. Diagnosed or treated for malignancy other than MDS or AML, except: a. Malignancy treated with curative intent and with no known active disease present for 3 years before day 1 of C1 b. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease c. Adequately treated cervical carcinoma in situ without evidence of disease
8. Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of day 1 of C1, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification
9. Known history of human immunodeficiency virus (HIV) or any uncontrolled active systemic infection requiring IV antibiotics
10. Active systemic hepatitis infection requiring treatment (carriers of hepatitis virus are permitted to enter the study), or known acute or chronic liver disease including cirrhosis
11. Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator’s opinion, could compromise the subject’s safety, interfere with the imetelstat metabolism, or put the study outcomes at undue risk; Subject has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments
12. Females who are pregnant or are currently breastfeeding or planning to become pregnant while enrolled in this study or within 3 months after the end of dosing
13. Subject is a man who plans to father a child while enrolled in this study or within 3 months after the end of dosing

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. • Overall response rate assessed after 4 months of treatment Using combined response assessment criteria for MDS and AML based on IWG 2018 criteria (MDS)1 and the criteria of the European LeukemiaNet (AML)2

Secondary endpoints 6

1. • Toxicity as measured by NCI CTCAE v5.0
2. • Overall survival - defined as the time from the beginning of imetelstat treatment until death or censored at the date of the last follow-up visit.
3. • Progression-free-survival - defined as the duration of time from time of imetelstat treatment to time of progression or death, whichever occurs first. A subject who has neither progressed nor died will be censored on the date of last follow-up visit.
4. • Duration of best overall response - measured from the time measurement criteria are met for CR, CRri, PR or SD (whichever is recorded first, defined in Appendix III) until the first date at which recurrent or progressive disease is objectively documented.
5. • Best overall response - defined as the best response recorded from the start of the imetelstat treatment until disease progression (taking as reference for progressive disease the smallest measurements recorded since the treatment started).
6. • Scores of EORTC QLQ-C30 (version 3) - Global health status / QoL - Functional scales - Symptom scales / items

Investigational products

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

Test 1

Auxiliary 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Gcp-Service International West GmbH

Sponsor organisation

Gcp-Service International West GmbH

Address

Siegfeldstrasse 11

City

Siegburg

Postcode

53721

Country

Germany

Scientific contact point

Organisation

Gcp-Service International West GmbH

Contact name

sponsor representative

Public contact point

Organisation

Gcp-Service International West GmbH

Contact name

sponsor representative

Third parties 5

Locations

2 EU/EEA countries · 8 investigational sites

By country

Investigational sites

Application history

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