Phase IPrimary Objective- To define the recommended phase II dose (RP2D) of selumetinib/dexamethasone combination in adult and paediatric patients with relapsed/refractory, RAS pathway mutant ALLSecondary Objectives- To evaluate safety and…
ID
Source
Brief title
Condition
- Leukaemias
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Phase I
Primary endpoints:
- The selection of RP2D based on dual primary measures of dose limiting
toxicities (DLT) and PK (ΔAUC)
Phase II
Primary endpoints:
- Response rate
Secondary outcome
Secondary endpoints Phase 1:
- Toxicity evaluation; PK variables of selumetinib in combination with
dexamethasone; response to treatment
Secondary endpoints Phase 2:
- Toxicity evaluation; PK variables of selumetinib in combination with
dexamethasone; difference in PK of selumetinib as single agent and in
combination with dexamethasone
Phase I/II
Research (tertiary) endpoints
- Exploratory PD biomarker studies, if clinical responses are observed
Background summary
Acute lymphoblastic leukaemia (ALL) is the most common childhood cancer, with
incidence in the UK of 2.8-6 per year per 100,000 population for children
between 0-9 years, and incidence of 0.9-2.1 for the age group between 10-19
years. While the overall cure rate for newly diagnosed paediatric ALL is
approaching 90%, children with relapsed ALL (rALL) are still facing a poor
outlook, with reported event free survival rates of 30-50%, and rALL remains a
frequent cause of death. In adults, the frequency of ALL is significantly
lower, with a UK incidence of 0.5-1 per 100,000 population in the 20-40 year
age group rising to 1-2 per 100,000 in the >70 age years population. ALL in
adulthood has proven to be more challenging to treat compared to childhood ALL
with the disease being more resistant to chemotherapy, and patients have a
reduced treatment tolerance especially in the elderly population. Only 40-50%
of patients less than 60 years old will survive 5 years, and overall survival
in elderly patients is significantly worse. Overall survival for rALL in adult
patients is less than 10% if treated with chemotherapy alone, and about 20% if
patients can undergo an allogeneic haematopoietic stem cell transplantation
(HSCT).
Advancements in knowledge about cancer biology have identified key pathways
like the RAS/RAF/MEK/ERK signalling cascade. This pathway has a central role in
transducing signals from the cell surface to intracellular targets, and has
been shown to harbour activating somatic mutations in a large proportion of
patients with newly diagnosed and relapsed ALL[3,9]. Patients with relapsed ALL
carrying RAS-pathway activating mutations (KRAS, NRAS, FLT3 and PTPN11)
comprised 38% of all relapsed patients[3], and they were associated with high
risk features (lower incidence of favourable cytogenetics, ETV6-RUNX1, early
relapse/relapse on treatment, CNS disease at relapse).
Selumetinib is a potent and selective allosteric MEK1/2 inhibitor which has
been evaluated in Phase II/III clinical trials for a number of cancers,
including BRAF mutation-positive melanoma, metastatic uveal melanoma,
pancreatic, colorectal, KRAS mutation-positive NSCLC. It has a favourable
toxicity profile (common side effects: diarrhoea, nausea/vomiting, rash,
swelling of face/extremities) and has demonstrated anti-tumour activity as a
monotherapy. In some adult cancers like advanced non-small-cell lung cancer
however, it has greater efficacy in combination, e.g. with docetaxel.
Follow up on the Irving data has shown very strong synergy between selumetinib
and the synthetic glucocorticoid dexamethasone, both in vitro and in the
orthotopic primagraft mouse model. Glucocorticosteroids (GC) such as
dexamethasone, are pivotal agents in the treatment of all lymphoid malignancies
due their ability to specifically induce apoptosis in developing lymphocytes,
and induction of proapoptotic BIM is key to this affect. BIM is inactivated by
ERK phosphorylation, and benchmark MEK inhibitors have demonstrated synergy
with GC in ALL cell line models in vitro. Using mutant ALL cell lines and
primagraft cells sensitive to selumetinib and highly resistant to GC (GI50>10
µM), the Irving group has demonstrated very strong synergy in vitro with these
drugs, with a Combination Index of <0.1 and a corresponding enhancement of BIM
induction, suggesting co-exposure may be highly effective for the treatment of
RAS pathway activated ALL.
The in vitro synergy observed with selumetinib and dexamethasone has been
confirmed in an orthotopic mouse model with three different RAS pathway mutant
ALL primagrafts, including KRAS mutated relapsed primary-derived cells. Weight
loss was observed in mice dosed with dexamethasone, resulting in a decrease in
the ideal dose of 1 mg/kg twice per day (BD) to 0.25 mg/kg once per day (QD).
There was no additional weight loss with the drug combination. Associated
pharmacodynamic experiments confirmed the mechanism of action of both drugs,
and the enhancement of BIM induction with the drug combination.
Preclinical evaluation of selumetinib has shown differential sensitivity in RAS
pathway mutated primary ALL cells compared to wild type cells in vitro and this
was mirrored in vivo using a xenograft model[3]. This is an orthotopic system
in which NOD SCID gamma null mice are engrafted with primary-derived
(primagraft) ALL cells which recapitulates the human disease.
Selumetinib-treated mice engrafted with RAS pathway mutated primagraft ALL
cells showed significantly reduced levels of peripheral, spleen and CNS ALL
compared to animals treated with vehicle control, and importantly no activity
was seen with RAS wildtype primagraft cells.
In addition, animals engrafted with RAS-mutant cells and treated with vehicle
control showed extensive CNS disease during postmortem examination, whereas in
animals treated with selumetinib that was significantly reduced.
The pharmacodynamic analyses after selumetinib dosing in vivo showed an
abrogation of the p-ERK signal indicating inhibition of ERK, and induction of
apoptosis with an increased signal for BIM and cleaved PARP.
Study objective
Phase I
Primary Objective
- To define the recommended phase II dose (RP2D) of selumetinib/dexamethasone
combination in adult and paediatric patients with relapsed/refractory, RAS
pathway mutant ALL
Secondary Objectives
- To evaluate safety and tolerability, and analyse pharmacokinetics (PK)
Phase II
Primary Objective
- To assess the preliminary anti-leukemic activity of the combination in
relapsed/refractory, RAS pathway-mutant ALL patients
Secondary Objectives
- To evaluate safety and tolerability, and analyse PK
Study design
An international, two-phase, two-group dose finding design, to include
paediatric and adult patients: phase I for dose finding; phase II for dose
expansion. Group P will enrol all patients under 18 years of age and Group A
will enrol all patients who are 18 years or older.
Intervention
Patients will receive selumetinib on cycle 1 day 1, then continuously from
cycle 1 day 4 onwards, combined with dexamethasone which will be administered
as a pulsed dose on days 2-4, 8-11, 15-18 and 22-25 during cycle 1.The pulsed
dose for dexamethasone will continue on days 1-4 during cycle two, then on days
1-5 for any subsequent cycles. Dose levels for each cohort will be determined
throughout phase I using a statistical model, observation of dose limiting
toxicities, and pharmacokinetic analysis. Phase II patients will be
administered the recommended phase II dose determined from the phase I part of
the trial using the same schedule.
Study burden and risks
ALL is the most common malignancy of childhood. Although the majority of
children with newly diagnosed ALL will achieve a complete remission,
approximately 20% will experience a relapse. The remission rates of relapsed
ALL are less than the rates for newly diagnosed ALL, which demonstated the need
for novel agents to improve outcomes for patients with relapsed disease.
Current standard of care therapies for ALL include dexamethasone. The addition
of a MEK inhibitor in patients with a RAS-pathway mutation could further boost
clinical response through a mechanism of action that differs from the current
chemotherapy.
The safety profile of selumetinib in children and adults for different
indicators seems mild and include rash, diarrhea, feeling sick or tired,
swollen extremities and face. A complete overview of the adverse effects are
found in the investigator brochure (IB).
Edgbaston -
Birmingham B152TT
GB
Edgbaston -
Birmingham B152TT
GB
Listed location countries
Age
Inclusion criteria
• Morphologically proven relapsed/refractory (M2 or M3 marrow; >=1st relapse for
adults, >=2nd relapse in paediatric group - see 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:
o Have received CAR -T cell therapy, or
o Be awaiting CAR -T cell therapy, or
o 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:
o Group A: Serum creatinine <1.5 x upper limit of normal (ULN)
o Group P as follows:
* <= 5 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 (Appendix 6); Group P - Lansky play scale >=60% (Appendix 7) or Karnofsky
scale >=60% (Appendix 8)
• Women of childbearing potential (see section 7.9.1 for definition) must have
a negative pregnancy test
• Patients who are women of childbearing potential and male patients with
partners who are women of child bearing potential must agree to use appropriate
contraception (see section 7.9.1 for definition) whilst on trial.
• Written informed consent
• Absence of any psychological, familial, sociological or geographical factors
potentially hampering compliance with the trial protocol and follow-up
schedule; those conditions should be discussed with the patient before
registration in the trial
• Patients who relapse or progress after HSCT need to be at least at day +100,
with no signs of Graft versus Host Disease and off immunosuppressive therapy
for at least one week.
• Patients who relapse or progress after CAR T cell therapy should be at least
4 weeks after infusion of CAR T cells.
• Patients must have a body surface area (BSA) >= 0.55 m2.
Exclusion criteria
• 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
o Prior or current cardiomyopathy including but not limited to the following:
* Known hypertrophic cardiomyopathy
* Known arrhythmogenic right ventricular cardiomyopathy
o Even if full recovery has occurred, previous moderate or severe impairment of
left ventricular systolic function (LVEF <45% on 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)
o Severe valvular heart disease
o Severe congential heart disease
o 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 Appendices 8 and 9)
Group A
o Baseline (LVEF) below the lower limit of normal (LLN) or <55% measured by ECHO
o Acute coronary syndrome within 6 months prior to trial registration
o Uncontrolled Angina - Canadian Cardiovascular Society grade II-IV despite
medical therapy (Appendix 11)
o Symptomatic heart failure New York Heart Association (NYHA) Class II-IV,
prior or current cardiomyopathy, or severe valvular heart disease (Appendix 12)
o Atrial fibrillation with a ventricular rate >100 bpm on Electrocardiogram
(ECG) at rest
o QTcF >450ms in male patients or >=460ms in female patients, or other factors
that increase the risk of QT prolongation
Group P
o Baseline SF <29%
o Atrial fibrillation with a ventricular rate >130 bpm on Electrocardiogram
(ECG) at rest
o QTcF >450ms in patients <12 years or >=460ms in patients >=12 but <18 years
• Ophthalmological conditions as follows:
o Current or past history of retinal pigment epithelial detachment
(RPED)/central serous retinopathy (CSR) or retinal vein occlusion
o Intraocular pressure (IOP) > 21 mmHg or uncontrolled glaucoma (irrespective
of IOP)
• Pregnant and breast feeding females
• Known severe hypersensitivity to selumetinib, dexamethasone or combination
medications or any excipient of these medicinal products, or history of
allergic reactions attributed to compounds of similar chemical or biologic
composition to selumetinib
• Have received or are receiving an IMP or other systemic anti-cancer
treatment (not including dexamethasone, prednisolone or hydroxycarbamide)
within 4 weeks (6 weeks for nitrosoureas, mitomycin, and suramin) prior to
trial registration, or within a period during which the IMP or systemic
anticancer treatment has not been cleared from the body (e.g. a period of 5
*half-lives*), whichever is the most appropriate and as judged by the
investigator
• Have had recent major surgery within a minimum 4 weeks prior to trial
registration, with the exception of surgical placement of vascular access
• Have received radiation therapy within 4 weeks prior to trial registration,
or limited field of radiation for palliation within 7 days of the first dose of
trial treatment
• Laboratory values as listed below (SI units):
o Serum bilirubin >1.5 x ULN (unless due to Gilbert*s syndrome)
• Have evidence of any other significant clinical disorder or laboratory
finding that, as judged by the investigator, makes it undesirable for the
patient to participate in the trial.
• Have any evidence of a severe or uncontrolled systemic disease (e.g.
unstable or uncompensated respiratory, cardiac, hepatic, or renal disease,
active infection (including hepatitis B, hepatitis C, HIV), active bleeding
diatheses, or renal transplant)
• Have refractory nausea and vomiting, chronic gastrointestinal diseases
(e.g., inflammatory bowel disease), or significant bowel resection that would
adversely affect the absorption/bioavailability of the orally administered
trial medication
• Any other active malignancy which, in the opinion of the investigator would
limit the ability of the patient to complete the study
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2016-003904-29-NL |
| ISRCTN | ISRCTN92323261 |
| CCMO | NL64779.041.19 |