International Trial of Selumetinib in Combination With Dexamethasone for the Treatment of Acute Lymphoblastic Leukaemia

NCT03705507 | Terminated Phase 1 DMC

• 3 other identifiers: RG_16-1862016-003904-29ISRCTN92323261
• Study Type: interventional
• Target: 12
• Locations: 3 countries
• Sites: 17

Brief Summary

This trial is to investigate the combination of selumetinib and dexamethasone in the treatment of acute lymphoblastic leukaemia (ALL) in both adults and children. Phase I is to find the most suitable dose of selumetinib to safely give with dexamethasone. Phase II will use this dose to find out how well the combination works.

Conditions

Acute Lymphoblastic Leukemia; Acute Lymphoblastic Leukemia, Adult; Acute Lymphoblastic Leukemia, Pediatric; Acute Lymphoblastic Leukemia, in Relapse; Acute Lymphoblastic Leukemia Recurrent

Outcome Measures

Primary Outcomes (3)

• Phase I: The occurrence/non-occurrence of dose limiting toxicities (DLTs) in the trial defined assessment period

  During cycle 1 (each cycle is 28 days)

• Phase II: Response to treatment as measured by morphological response

  At the end of cycle 1 (each cycle is 28 days)

• Phase II: For patients with CNS involvement only response to treatment as measured by clearance of Cerebral Spinal Fluid (CSF) blasts

  At the end of cycle 1 (each cycle is 28 days)

Secondary Outcomes (13)

• Phase I & II: The occurrence of adverse events (AEs) as measured by Common Terminology Criteria for Adverse Events (CTCAE) version 4

  From cycle 1 day 1 until 28 days after End of Treatment (6 cycles, each cycle is 28 days)

• Phase I & II: The occurrence of adverse events (AEs) as measured by causality assessment

  From cycle 1 day 1 until 28 days after the last treatment (6 cycles, each cycle is 28 days)

• Phase I & II: Pharmacokinetic variables of selumetinib in combination with dexamethasone from the concentration time profile measured by area under the plasma concentration versus time curve (AUC)

  At cycle 1 day 1, cycle 1 day 4 and cycle 2 day 1 (each cycle is 28 days)

• Phase I & II: Pharmacokinetic variables of selumetinib in combination with dexamethasone from the concentration time profile measured by the peak plasma concentration (Cmax)

  At cycle 1 day 1, cycle 1 day 4 and cycle 2 day 1 (each cycle is 28 days)

• Phase I & II: Pharmacokinetic variables of selumetinib in combination with dexamethasone from the concentration time profile measured by the time to reach peak plasma concentration (Tmax)

  At cycle 1 day 1, cycle 1 day 4 and cycle 2 day 1 (each cycle is 28 days)

Other Outcomes (1)

• Exploratory pharmacodynamic biomarker studies including levels of phosphorylated Extracellular signal-regulated kinase (ERK) by flow cytometry as well as retrospective messenger ribonucleic acid (mRNA) profiling, including Bcl-2-like protein 11 (BIM)

  Cycle 1 day 1, cycle 1 day 4 and End of Treatment (6 cycles, each cycle is 28 days)

Study Arms (2)

Selumetinib + Dexamethasone - Group A (18 years and above)

EXPERIMENTAL

Patients will receive the adult cohort specified dose of selumetinib by mouth, as a single dose on cycle 1 day 1, then twice daily continuously from cycle 1 day 4 onwards. Combined with pulsed doses of dexamethasone at 6mg/m2/day on days 2-4 and 8-11 then at 4mg/m2/day on days 15-18 and 22-25 divided into two doses (as per local practice) by mouth during cycle 1, then on days 1-4 at 4mg/m2/day at the start of cycle 2, then on days 1-5 at 6mg/m2/day during subsequent cycles.

Drug: Selumetinib; Drug: Dexamethasone

Selumetinib + Dexamethasone - Group P (under 18 years)

EXPERIMENTAL

Patients will receive the paediatric cohort specified dose of selumetinib by mouth, as a single dose on cycle 1 day 1, then twice daily continuously from cycle 1 day 4 onwards. Combined with pulsed doses of dexamethasone at 6mg/m2/day on days 2-4 and 8-11 then at 4mg/m2/day on days 15-18 and 22-25 divided into two doses (as per local practice) by mouth during cycle 1, then on days 1-4 at 4mg/m2/day at the start of cycle 2, then on days 1-5 at 6mg/m2/day during subsequent cycles.

Drug: Selumetinib; Drug: Dexamethasone

Interventions

Selumetinib DRUG

Selumetinib is a small molecule inhibitor of the MEK protein

Also known as: AZD6244

Selumetinib + Dexamethasone - Group A (18 years and above); Selumetinib + Dexamethasone - Group P (under 18 years)

Dexamethasone DRUG

Steroid used for the treatment and management of a number of conditions including cancers and leukaemias.

Selumetinib + Dexamethasone - Group A (18 years and above); Selumetinib + Dexamethasone - Group P (under 18 years)

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Morphologically proven relapsed/refractory (M2 or M3 marrow; ≥1st relapse for adults, ≥2nd relapse in paediatric group - see Protocol Appendix 5) or progressive B cell precursor or T-Acute Lymphoblastic Leukaemia (ALL) with demonstrated RAS pathway activating mutations (NRAS, KRAS, FLT3, PTPN11, cCBL, NF1, BRAF, IKZF2, IKZF3, IL7Rα or JAK1) identified during the trial screening process
• B cell precursor patients must either:
• Have received CAR -T cell therapy, or
• Be awaiting CAR -T cell therapy, or
• Be considered ineligible for CAR -T cell therapy
• Group P (paediatric): \<18 years of age; Group A (adult): ≥18 years of age
• Adequate renal function:
• Group A: Serum creatinine \<1.5 x upper limit of normal (ULN)
• Group P as follows:
• years: Serum creatinine \<0.8 mg/dL or 70 μmol/L, \> 5 years but ≤ 10 years: Serum creatinine \<1 mg/dL or 88 μmol/L, \> 10 years but ≤ 15 years: Serum creatinine \<1.2 mg/dL or 106 μmol/L, \> 15 years: Serum creatinine \<1.5 mg/dL or 132 μmol/L
• Patient is able to swallow selumetinib capsules whole
• Performance status (PS): Group A - Eastern Cooperative Oncology Group (ECOG) ≤2 (Protocol Appendix 6); Group P - Lansky play scale ≥60% (Protocol Appendix 7) or Karnofsky scale ≥60% (Appendix 8)
• Women of childbearing potential (see protocol section 7.9.3 for definition) must have a negative pregnancy test
• Patients who are women of childbearing potential and male patients with partners who are women of childbearing potential must agree to use appropriate contraception (see protocol section 7.9.3 for definition) whilst on trial
• Written informed consent

You may not qualify if:

• ALL without presence of RAS-pathway activating mutations
• Mature B-cell leukaemia and Philadelphia positive ALL
• Prior exposure to MEK, RAS or RAF inhibitors
• Any unresolved toxicity ≥ CTCAE Grade 2 from previous anti-cancer therapy, except for alopecia
• Cardiac conditions as follows:
• Group A and P
• Prior or current cardiomyopathy including but not limited to the following:
• Known hypertrophic cardiomyopathy
• Known arrhythmogenic right ventricular cardiomyopathy
• Even if full recovery has occurred, previous moderate or severe impairment of left ventricular systolic function (LVEF \<45% on Echocardiogram (ECHO) in Group A; SF \<29% in Group P but excluding transient impairments due to e.g. anaemia/sepsis or results not thought to represent a true reflection of cardiac function)
• Severe valvular heart disease
• Severe congenital heart disease
• Uncontrolled hypertension:
• Group A: BP ≥150/95 mmHg despite medical therapy
• Group P: BP ≥95th percentile for age, height and gender (please refer to Blood Pressure by Age and Height Percentiles tables in Protocol Appendices 8 and 9) Group A

Sponsors & Collaborators

• University of Birmingham: lead
• Cancer Research UK: collaborator
• AstraZeneca: collaborator

Study Sites (17)

Rigshospitalet

Copenhagen, DK-2100, Denmark

Location

Prinses Maxima Centrum Voor Kinderoncologie

Utrecht, 3584 CS, Netherlands

Location

Queen Elizabeth Hospital

Birmingham, B15 2TH, United Kingdom

Location

Birmingham Children's Hospital

Birmingham, B4 6NH, United Kingdom

Location

Beatson West of Scotland Cancer Centre

Glasgow, G12 0YN, United Kingdom

Location

Alder Hey Children's Hospital

Liverpool, L12 2AP, United Kingdom

Location

University College Hospital Adult Unit

London, NW1 2PG, United Kingdom

Location

University College Hospital Paediatric/Teenage & Young Adult Unit

London, NW1 2PG, United Kingdom

Location

King's College Hospital

London, SE5 9RS, United Kingdom

Location

Hammersmith Hospital

London, W12 0HS, United Kingdom

Location

Great Ormond Street Hospital

London, WC1N 3JH, United Kingdom

Location

The Christie Hospital

Manchester, M20 4BX, United Kingdom

Location

Great North Children's Hospital, Royal Victoria Infirmary

Newcastle, NE1 4LP, United Kingdom

Location

Freeman Hospital

Newcastle, NE7 7DN, United Kingdom

Location

Royal Hallamshire Hospital

Sheffield, S10 2JF, United Kingdom

Location

Department of Paediatric Oncology, Royal Marsden Hospital, Sutton

Sutton, SM2 5PT, United Kingdom

Location

Haemato-Oncology Adult Unit, Royal Marsden Hospital, Sutton

Sutton, SM2 5PT, United Kingdom

Location

Related Publications (1)

• Menne T, Slade D, Savage J, Johnson S, Irving J, Kearns P, Plummer R, Shenton G, Veal GJ, Vormoor B, Vormoor J, Billingham L. Selumetinib in combination with dexamethasone for the treatment of relapsed/refractory RAS-pathway mutated paediatric and adult acute lymphoblastic leukaemia (SeluDex): study protocol for an international, parallel-group, dose-finding with expansion phase I/II trial. BMJ Open. 2022 Mar 4;12(3):e059872. doi: 10.1136/bmjopen-2021-059872.

  PMID: 35246426 BACKGROUND

Related Links

• Trial Website

MeSH Terms

Conditions

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Interventions

AZD 6244; Dexamethasone

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated

Study Officials

• Tobias Menne

  The Newcastle Hospitals NHS Foundation Trust

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Group P will enrol all patients under 18 years of age and Group A will enrol all patients who are 18 years or older.

Study Record Dates

• First Submitted: July 4, 2018
• First Posted: October 15, 2018
• Study Start: May 18, 2018
• Primary Completion: May 3, 2023
• Study Completion: May 3, 2023
• Last Updated: May 11, 2023

Record last verified: 2023-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, ANALYTIC CODE
• Time Frame: Data will be available within 6 months of the primary publication.
• Access Criteria: See Plan Description above.

Locations

DK (1); GB (15); NL (1)