NCT01809210: SELECT-3

Assess Safety & Efficacy of Selumetinib When Given in Combination With Standard First Line Treatment for Advanced Non-small Cell Lung Cancer

Completed Phase 1 Results posted Last updated 13 March 2018

What this trial tests

Phase 1 trial testing selumetinib in Locally Advanced or Metastatic NSCL Cancer Stage IIIB IV in 55 participants. Completed in 4 January 2016.

Timeline

4 April 2013

Primary endpoint
4 January 2016

4 January 2016

Quick facts

Lead sponsor	AstraZeneca
Phase	Phase 1
Status	Completed
Study type	INTERVENTIONAL
Allocation	na
Design	single group
Masking	none
Primary purpose	treatment
Enrollment	55
Start date	4 April 2013
Primary completion	4 January 2016
Estimated completion	4 January 2016
Sites	4 locations across United Kingdom

Drugs / interventions tested

• selumetinib — full drug profile →
• gemcitabine
• cisplatin (cisplatin) — full drug profile →
• carboplatin (Carboplatin) — full drug profile →
• pemetrexed — full drug profile →

Conditions studied

• Locally Advanced or Metastatic NSCL Cancer Stage IIIB IV — all drugs for Locally Advanced or Metastatic NSCL Cancer Stage IIIB IV →

Sponsor

AstraZeneca — full company profile →

Who can join

Adults 18 to 99, any sex, with Locally Advanced or Metastatic NSCL Cancer Stage IIIB IV. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Dose Limiting Toxicity (DLT) Events in Chemotherapy in Combination With Selumetinib Primary · The first dose on Cycle 1 Day 1 up to the time before dosing on Cycle 2 Day 1, assessed up to 3 weeks

Any toxicity not attributable to the disease or disease-related processess under investigation, considered related to the combination of chemotherapy plus selumetinib, which occurs within the timeframe and is dose limiting

Evaluable patients

Group	Value	95% CI
Cohort 1 sel50, Gem, Cis	3
Cohort 2 sel50, Gem, Carb	7
Cohort 3 sel75, Gem, Cis	4
Cohort 4 sel150, Pem, Carb	3
Cohort 5 sel75, Pem, Carb	6
Cohort 6 sel75, Pem, Cis	12
Cohort 7 sel100, Pem, Carb	6

Evaluable patients with a DLT Event

Group	Value	95% CI
Cohort 1 sel50, Gem, Cis	0
Cohort 2 sel50, Gem, Carb	2
Cohort 3 sel75, Gem, Cis	1
Cohort 4 sel150, Pem, Carb	0
Cohort 5 sel75, Pem, Carb	0
Cohort 6 sel75, Pem, Cis	1
Cohort 7 sel100, Pem, Carb	1

Best Objective Response Secondary · Screening, week 6 and week 12

The best response a patient has had during their time in the study up until RECIST progression or last valuable assessment in the absence of RECIST progression. Per Response Evaluation Criteria In Solid Tumours (RECIST version 1.1) for target lesions (TL) and assessed by MRI or CT: Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for a Partial Response nor sufficient increase to qualify for Progressive Disease (PD); Progressive Disease (PD), \>=20% increase in the sum of the longest diamete

Complete response

Group	Value	95% CI
Cohort 1 sel50, Gem, Cis	0
Cohort 2 sel50, Gem, Carb	0
Cohort 3 sel75, Gem, Cis	0
Cohort 4 sel150, Pem, Carb	0
Cohort 5 sel75, Pem, Carb	0
Cohort 6 sel75, Pem, Cis	0
Cohort 7 sel100, Pem, Carb	0

Partial response

Group	Value	95% CI
Cohort 1 sel50, Gem, Cis	1
Cohort 2 sel50, Gem, Carb	2
Cohort 3 sel75, Gem, Cis	2
Cohort 4 sel150, Pem, Carb	1
Cohort 5 sel75, Pem, Carb	1
Cohort 6 sel75, Pem, Cis	2
Cohort 7 sel100, Pem, Carb	2

Unconfirmed complete or partial response

Group	Value	95% CI
Cohort 1 sel50, Gem, Cis	0
Cohort 2 sel50, Gem, Carb	3
Cohort 3 sel75, Gem, Cis	0
Cohort 4 sel150, Pem, Carb	0
Cohort 5 sel75, Pem, Carb	2
Cohort 6 sel75, Pem, Cis	2
Cohort 7 sel100, Pem, Carb	2

Stable disease

Group	Value	95% CI
Cohort 1 sel50, Gem, Cis	0
Cohort 2 sel50, Gem, Carb	1
Cohort 3 sel75, Gem, Cis	2
Cohort 4 sel150, Pem, Carb	2
Cohort 5 sel75, Pem, Carb	3
Cohort 6 sel75, Pem, Cis	7
Cohort 7 sel100, Pem, Carb	6

RECIST progression

Group	Value	95% CI
Cohort 1 sel50, Gem, Cis	2
Cohort 2 sel50, Gem, Carb	0
Cohort 3 sel75, Gem, Cis	1
Cohort 4 sel150, Pem, Carb	0
Cohort 5 sel75, Pem, Carb	0
Cohort 6 sel75, Pem, Cis	1
Cohort 7 sel100, Pem, Carb	1

Death

Group	Value	95% CI
Cohort 1 sel50, Gem, Cis	0
Cohort 2 sel50, Gem, Carb	0
Cohort 3 sel75, Gem, Cis	0
Cohort 4 sel150, Pem, Carb	0
Cohort 5 sel75, Pem, Carb	0
Cohort 6 sel75, Pem, Cis	1
Cohort 7 sel100, Pem, Carb	0

Incomplete post-baseline assessments

Group	Value	95% CI
Cohort 1 sel50, Gem, Cis	0
Cohort 2 sel50, Gem, Carb	3
Cohort 3 sel75, Gem, Cis	2
Cohort 4 sel150, Pem, Carb	0
Cohort 5 sel75, Pem, Carb	0
Cohort 6 sel75, Pem, Cis	2
Cohort 7 sel100, Pem, Carb	1

Percentage Change From Baseline at 6 Weeks in Target Lesion Size Secondary · Week 6

The percentage change in the sum of the diameters of target lesions

Group	Value	95% CI
Cohort 1 sel50, Gem, Cis	-7.5	± 19.79
Cohort 2 sel50, Gem, Carb	-29.3	± 11.15
Cohort 3 sel75, Gem, Cis	-10.4	± 24.45
Cohort 4 sel150, Pem, Carb	-14.7	± 1.91
Cohort 5 sel75, Pem, Carb	-24.4	± 32.60
Cohort 6 sel75, Pem, Cis	-18.9	± 10.55
Cohort 7 sel100, Pem, Carb	-18.4	± 19.58

Best Percentage Change From Baseline in Target Lesion Size Secondary · Screening, week 6 and week 12

The best percentage change in tumour size a patient has had during their time in the study up until RECIST progression or last valuable assessment in the absence of RECIST progression. Percentage change was derived at each visit by the percentage change in the sum of the diameters of target lesions

Group	Value	95% CI
Cohort 1 sel50, Gem, Cis	-11.9	± 26.52
Cohort 2 sel50, Gem, Carb	-34.6	± 8.11
Cohort 3 sel75, Gem, Cis	-41.3	± 21.25
Cohort 4 sel150, Pem, Carb	-28.3	± 15.25
Cohort 5 sel75, Pem, Carb	-34.7	± 33.30
Cohort 6 sel75, Pem, Cis	-24.4	± 14.71
Cohort 7 sel100, Pem, Carb	-25.4	± 20.51

Objective Response Rate (ORR) Secondary · Up until progression or last evaluable assessment in the absence of progression, up to 9 months

The number of patients who had at least 1 confirmed visit response of Complete Response (CR) or Partial Response (PR) prior to any evidence of progression. Per Response Evaluation Criteria In Solid Tumours (RECIST version 1.1) for target lesions (TL) and assessed by MRI or CT: Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Complete Response (CR), disappearance of all target lesions, any pathological lymph nodes selected as TLs must have a reduction in short axis to \<10mm; Objective Response Rate (ORR) = CR + PR

Group	Value	95% CI
Cohort 1 sel50, Gem, Cis	1	± 26.52
Cohort 2 sel50, Gem, Carb	2	± 8.11
Cohort 3 sel75, Gem, Cis	2	± 21.25
Cohort 4 sel150, Pem, Carb	1	± 15.25
Cohort 5 sel75, Pem, Carb	1	± 33.30
Cohort 6 sel75, Pem, Cis	2	± 14.71
Cohort 7 sel100, Pem, Carb	2	± 20.51

AUC (0-tau) Secondary · Cycle 2 Day1, pre-dose, 0.5, 1, 1.5, 2, 4, 8, 10 hours post dose

Area under the concentration time curve (AUC) over a dosing interval at steady state (0-tau)

Group	Value	95% CI
Cohort 1 sel50, Gem, Cis	NA	± NA
Cohort 2 sel50, Gem, Carb	3571	± 42.13
Cohort 3 sel75, Gem, Cis	3339	± 15.08
Cohort 4 sel150, Pem, Carb	4813	± 30.93
Cohort 5 sel75, Pem, Carb	4366	± 48.14
Cohort 6 sel75, Pem, Cis	4116	± 33.92
Cohort 7 sel100, Pem, Carb	5202	± 52.94

Cmax,ss Secondary · Cycle 2 Day1, pre-dose, 0.5, 1, 1.5, 2, 4, 8, 10 hours post dose

Maximum plasma concentration at steady state

Group	Value	95% CI
Cohort 1 sel50, Gem, Cis	476.7	± 51.12
Cohort 2 sel50, Gem, Carb	1222	± 59.86
Cohort 3 sel75, Gem, Cis	1487	± 23.09
Cohort 4 sel150, Pem, Carb	1615	± 27.71
Cohort 5 sel75, Pem, Carb	1375	± 40.21
Cohort 6 sel75, Pem, Cis	1364	± 57.78
Cohort 7 sel100, Pem, Carb	2309	± 35.99

Tmax,ss Secondary · Cycle 2 Day1, pre-dose, 0.5, 1, 1.5, 2, 4, 8, 10 hours post dose

Time to reach maximum plasma concentration at steady state

Group	Value	95% CI
Cohort 1 sel50, Gem, Cis	1.00	1.00 – 1.60
Cohort 2 sel50, Gem, Carb	1.25	1.00 – 1.50
Cohort 3 sel75, Gem, Cis	1.00	0.58 – 1.00
Cohort 4 sel150, Pem, Carb	1.00	1.00 – 1.50
Cohort 5 sel75, Pem, Carb	1.75	0.50 – 2.03
Cohort 6 sel75, Pem, Cis	1.48	0.50 – 2.75
Cohort 7 sel100, Pem, Carb	1.50	1.00 – 2.00

CL/F Secondary · Cycle 2 Day1, pre-dose, 0.5, 1, 1.5, 2, 4, 8, 10 hours post dose

Apparent oral plasma clearance

Group	Value	95% CI
Cohort 1 sel50, Gem, Cis	NA	± NA
Cohort 2 sel50, Gem, Carb	14.72	± 5.156
Cohort 3 sel75, Gem, Cis	22.64	± 3.521
Cohort 4 sel150, Pem, Carb	10.72	± 3.328
Cohort 5 sel75, Pem, Carb	18.82	± 9.777
Cohort 6 sel75, Pem, Cis	19.08	± 5.881
Cohort 7 sel100, Pem, Carb	21.02	± 9.857

Adverse events — posted to ClinicalTrials.gov

Time frame: Adverse Events are collected throughout the study, from informed consent until the end of follow-up, which is defined as 28 +/- 7 days after selumetinib is discontinued. Patients were expected to receive up to 6 cycles (18 wks) of chemotherapy.. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Cohort 1 sel50, Gem, Cis

Serious: 1/3 (33%)

Deaths: —

Cohort 2 sel50, Gem, Carb

Serious: 6/9 (67%)

Deaths: —

Cohort 3 sel75, Gem, Cis

Serious: 3/7 (43%)

Deaths: —

Cohort 4 sel150, Pem, Carb

Serious: 2/3 (67%)

Deaths: —

Cohort 5 sel75, Pem, Carb

Serious: 3/6 (50%)

Deaths: —

Cohort 6 sel75, Pem, Cis

Serious: 9/15 (60%)

Deaths: —

Cohort 7 sel100, Pem, Carb

Serious: 9/12 (75%)

Deaths: —

Serious adverse events (34 terms)

Reaction	System	Cohort 1 sel50, Gem, Cis	Cohort 2 sel50, Gem, Carb	Cohort 3 sel75, Gem, Cis	Cohort 4 sel150, Pem, Carb	Cohort 5 sel75, Pem, Carb	Cohort 6 sel75, Pem, Cis	Cohort 7 sel100, Pem, Carb
Thrombocytopenia	Blood and lymphatic system disorders	—	—	—	—	—	—	—
Anaemia	Blood and lymphatic system disorders	—	—	—	—	—	—	—
Nausea	Gastrointestinal disorders	—	—	—	—	—	—	—
Febrile neutropenia	Blood and lymphatic system disorders	—	—	—	—	—	—	—
Neutropenia	Blood and lymphatic system disorders	—	—	—	—	—	—	—
Myocardial infarction	Cardiac disorders	—	—	—	—	—	—	—
Tachycardia	Cardiac disorders	—	—	—	—	—	—	—
Chorioretinopathy	Eye disorders	—	—	—	—	—	—	—
Retinal vein occlusion	Eye disorders	—	—	—	—	—	—	—
Duodenal ulcer	Gastrointestinal disorders	—	—	—	—	—	—	—
Large intestine perforation	Gastrointestinal disorders	—	—	—	—	—	—	—
Stomatitis	Gastrointestinal disorders	—	—	—	—	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—	—	—	—	—
Pyrexia	General disorders	—	—	—	—	—	—	—
Cellulitis	Infections and infestations	—	—	—	—	—	—	—
Lower respiratory tract infection	Infections and infestations	—	—	—	—	—	—	—
Mediastinitis	Infections and infestations	—	—	—	—	—	—	—
Neutropenic sepsis	Infections and infestations	—	—	—	—	—	—	—
Pneumonia	Infections and infestations	—	—	—	—	—	—	—
Upper respiratory tract infection	Infections and infestations	—	—	—	—	—	—	—
Transaminases increased	Investigations	—	—	—	—	—	—	—
Dehydration	Metabolism and nutrition disorders	—	—	—	—	—	—	—
Fluid overload	Metabolism and nutrition disorders	—	—	—	—	—	—	—
Hypoglycaemia	Metabolism and nutrition disorders	—	—	—	—	—	—	—
Musculoskeletal chest pain	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—	—

Other adverse events (174 terms — click to expand)

Reaction	System	Cohort 1 sel50, Gem, Cis	Cohort 2 sel50, Gem, Carb	Cohort 3 sel75, Gem, Cis	Cohort 4 sel150, Pem, Carb	Cohort 5 sel75, Pem, Carb	Cohort 6 sel75, Pem, Cis	Cohort 7 sel100, Pem, Carb
Nausea	Gastrointestinal disorders	—	—	—	—	—	—	—
Constipation	Gastrointestinal disorders	—	—	—	—	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—	—	—	—	—
Fatigue	General disorders	—	—	—	—	—	—	—
Rash	Skin and subcutaneous tissue disorders	—	—	—	—	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—	—	—	—	—
Neutropenia	Blood and lymphatic system disorders	—	—	—	—	—	—	—
Periorbital oedema	Eye disorders	—	—	—	—	—	—	—
Anaemia	Blood and lymphatic system disorders	—	—	—	—	—	—	—
Headache	Nervous system disorders	—	—	—	—	—	—	—
Lethargy	Nervous system disorders	—	—	—	—	—	—	—
Thrombocytopenia	Blood and lymphatic system disorders	—	—	—	—	—	—	—
Mouth ulceration	Gastrointestinal disorders	—	—	—	—	—	—	—
Oedema peripheral	General disorders	—	—	—	—	—	—	—
Lower respiratory tract infection	Infections and infestations	—	—	—	—	—	—	—
Oral candidiasis	Infections and infestations	—	—	—	—	—	—	—
Decreased appetite	Metabolism and nutrition disorders	—	—	—	—	—	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—	—
Epistaxis	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—	—
Leukopenia	Blood and lymphatic system disorders	—	—	—	—	—	—	—
Dyspepsia	Gastrointestinal disorders	—	—	—	—	—	—	—
Stomatitis	Gastrointestinal disorders	—	—	—	—	—	—	—
Depression	Psychiatric disorders	—	—	—	—	—	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—	—
Dry skin	Skin and subcutaneous tissue disorders	—	—	—	—	—	—	—
Hypertension	Vascular disorders	—	—	—	—	—	—	—
Tinnitus	Ear and labyrinth disorders	—	—	—	—	—	—	—
Vision blurred	Eye disorders	—	—	—	—	—	—	—
Gastrooesophageal reflux disease	Gastrointestinal disorders	—	—	—	—	—	—	—
Oral pain	Gastrointestinal disorders	—	—	—	—	—	—	—
Peripheral swelling	General disorders	—	—	—	—	—	—	—
Pyrexia	General disorders	—	—	—	—	—	—	—
Cellulitis	Infections and infestations	—	—	—	—	—	—	—
Conjunctivitis	Infections and infestations	—	—	—	—	—	—	—
Upper respiratory tract infection	Infections and infestations	—	—	—	—	—	—	—
Urinary tract infection	Infections and infestations	—	—	—	—	—	—	—
Dehydration	Metabolism and nutrition disorders	—	—	—	—	—	—	—
Hypomagnesaemia	Metabolism and nutrition disorders	—	—	—	—	—	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—	—

Most-reported serious reactions: Thrombocytopenia, Anaemia, Nausea, Febrile neutropenia, Neutropenia, Myocardial infarction, Tachycardia, Chorioretinopathy.

Data from ClinicalTrials.gov NCT01809210 adverse events section.

Sponsor's own description

This is a Phase I, open label multicentre study of selumetinib administered orally in combination with first line chemotherapy regimens to patients with advanced/metastatic NSCLC. The study has been designed to allow an investigation of the optimal dose of selumetinib in combination with various standard first line double-platinum chemotherapy regimens. Initial assessment will be based on tolerability of selumetinib in combination with one or more selected regimens that are considered to be tolerated also being assessed for preliminary evidence of activity.

This study is a dose finding and optional cohort expansion; In addition all patients will be assessed for anti-cancer efficacy of the combination of selumetinib and chemotherapy.

Publications & conference data

5 peer-reviewed publications reference this trial (live from Europe PMC):

1. MEK inhibitors for the treatment of non-small cell lung cancer.
   Han J, Liu Y, Yang S, Wu X, et al · · 2021 · cited 154× · PMID 33402199 · DOI 10.1186/s13045-020-01025-7
2. Clinical Pharmacokinetics and Pharmacodynamics of Selumetinib.
   Campagne O, Yeo KK, Fangusaro J, Stewart CF. · · 2021 · cited 35× · PMID 33354735 · DOI 10.1007/s40262-020-00967-y
3. SELECT-3: a phase I study of selumetinib in combination with platinum-doublet chemotherapy for advanced NSCLC in the first-line setting.
   Greystoke A, Steele N, Arkenau HT, Blackhall F, et al · · 2017 · cited 19× · PMID 28950288 · DOI 10.1038/bjc.2017.271
4. Personalizing therapy in advanced non-small cell lung cancer.
   Villaruz LC, Burns TF, Ramfidis VS, Socinski MA. · · 2013 · cited 15× · PMID 24258572 · DOI 10.1055/s-0033-1358552
5. Targeting the MEK signaling pathway in non-small cell lung cancer (NSCLC) patients with RAS aberrations.
   Abdel-Rahman O. · · 2016 · cited 13× · PMID 26893312 · DOI 10.1177/1753465816632111