Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Symptoms and General Pathology

Lung Neoplasms

Carcinoma, Non-Small-Cell Lung

Carcinoma

Shock

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

All Drugs and Chemicals

Antineoplastic Agents

Amino Acids

Mitogens

Afatinib

Tyrosine Kinase Inhibitors

Erlotinib Hydrochloride

Gefitinib

Tyrosine

Study Part 1: DS-2248 oral capsule(s) of increasing strength in a dose escalation study in subjects with advanced solid tumors, administered once daily in 21-day cycles, with no interruption between cycles if no unacceptable treatment-related toxicity or tumor progression is observed.

Study Part 2: DS-2248 oral capsule(s) dose of 4.5 mg/m\^2, in subjects with non-small cell lung cancer who have developed acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors or whose tumors carry an ALK translocation and are resistant to ALK inhibitor therapy, administered once daily in 21 day-cycles, with no interruption between cycles if no unacceptable treatment-related toxicity or tumor progression are observed.

Oral capsules, of various strengths (1, 5 , 20 ,or 50 milligrams), once daily during 21-day cycles, until unacceptable treatment-related toxicity or tumor progression are observed.

DS-2248

Global Clinical Leader

This phase 1 clinical trial is intended to understand the safety and tolerability of a new anticancer drug in subjects with advanced solid tumors. The patients who qualify for the study will receive a once daily dose of the drug taken by mouth and will undergo several tests to measure the drug in the blood and to understand the safety, tolerability and any effect of the drug on the tumor. The antitumor effect of the drug is not known in human.

The study will be conducted in two parts. Part 1 is a dose escalation study in which subjects in each cohort will be given increasing doses of the study drug until a maximum tolerated dose (MTD) or maximum administered dose (MAD) is determined as the recommended phase 2 dose (RP2D). The drug will be administered as oral capsules once daily in 21 day cycles, with no interruption between cycles if no unacceptable treatment-related toxicity or tumor progression are observed.

After determining the RP2D, Part 2 of the study, which is a dose expansion study will begin in which subjects with advanced non-small cell lung cancer who developed acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI), erlotinib, gefitinib, afatinib (and others) or whose tumors carry an ALK translocation and are resistant to ALK inhibitor therapy, will be treated with DS-2248 at RP2D. The drug will be administered as oral capsules once daily in 21 day cycles, with no interruption between cycles if no unacceptable treatment-related toxicity or tumor progression are observed.

A Study of DS-2248 in Participants With Advanced Solid Tumors

A Phase 1, Open-Label, Multiple-Ascending-Dose Study of DS-2248, an Orally Bioavailable Heat Shock Protein 90 Inhibitor, in Subjects With Advanced Solid Tumors

De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/

Objective response rate was defined as the sum of complete response (CR) and partial response (PR) rates. CR was defined as a disappearance of all target lesions; any pathological lymph nodes (whether target or non-target) must have had a reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

Complete response (CR) was defined as a disappearance of all target lesions; any pathological lymph nodes (whether target or non-target) must have had a reduction in short axis to \<10 mm. Partial response (PR) was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive disease (PD) was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this included the baseline sum if that was the smallest on study). In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 mm. Stable disease (SD) was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Objective response rate (ORR) was defined as the sum of CR and PR rates.

Disease control rate (DCR) was defined as the sum of complete response (CR) and partial response (PR) rates, and stable disease (SD) rate for a minimum of 12 weeks. Complete response (CR) was defined as a disappearance of all target lesions; any pathological lymph nodes (whether target or non-target) must have had a reduction in short axis to \<10 mm. Partial response (PR) was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable disease (SD) was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (at least a 20% increase in the sum of diameters of target lesions), taking as reference the smallest sum diameters while on study.

Duration of response measured from the time at which criteria were first met for complete (CR) or partial response (PR) until the first date that progressive disease (PD) was objectively documented. Participants who had not progressed at the data cut-off date were censored at their last evaluable tumor assessment date. Duration of stable disease (SD) measured from the date of enrollment until the first date that criteria for disease progression were met. The minimum time interval for the duration of SD was 6 weeks. Participants who had not progressed at the data cut-off date were censored at their last evaluable tumor assessment date.

Progression-free survival (PFS) defined as the time from the date of enrollment to the earlier of the dates of the first objective documentation of radiographic disease progression (as per RECIST V1.1) or death due to any cause. Participants who were alive with no objective documentation of (radiographic) disease progression by the data cut-off date were censored at the date of their last evaluable tumor assessment. Participants who were lost to follow-up or withdrew early from the study with no documented disease progression were censored at the last evaluable tumor assessment.

A treatment-emergent adverse event (TEAE) is defined as an adverse event that emerges during treatment, having been absent at pre-treatment; or reemerges during treatment, having been present at baseline but stopped prior to treatment; or worsens in severity after starting treatment relative to the pre-treatment state, when the AE is continuous. A DS-2248-related TEAE is an TEAE that is related to DS-2248 in the relationship.

Daiichi Sankyo UK Ltd.

Daiichi Sankyo

A treatment-emergent adverse event (TEAE) is defined as an adverse event (AE) that emerges during treatment, having been absent at pre-treatment; or reemerges during treatment, having been present at baseline but stopped prior to treatment; or worsens in severity after starting treatment relative to the pre-treatment state, when the AE is continuous.

Participants who received oral DS-2248 0.6 mg/m\^2 once daily.

Part 1, Cohort 1: DS-2248 0.6 mg/m^2

Participants who received oral DS-2248 1.2 mg/m\^2 once daily.

Part 1, Cohort 2: DS-2248 1.2 mg/m^2

Participants who received oral DS-2248 1.8 mg/m\^2 once daily.

Part 1, Cohort 3: DS-2248 1.8 mg/m^2

Participants who received oral DS-2248 2.7 mg/m\^2 once daily.

Part 1, Cohort 4: DS-2248 2.7 mg/m^2

Participants who received oral DS-2248 3.5 mg/m\^2 once daily.

Part 1, Cohort 5: DS-2248 3.5 mg/m^2

Participants who received oral DS-2248 4.5 mg/m\^2 once daily.

Part 1, Cohort 6: DS-2248 4.5 mg/m^2

Participants who received oral DS-2248 5.85 mg/m\^2 once daily.

Part 1, Cohort 7: DS-2248 5.85 mg/m^2

Participants who were epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-resistant and received oral 4.5 mg/m\^2 once daily.

Part 2, EGFR TKI-resistant: DS-2248 4.5 mg/m^2

Participants who were ALK-inhibitor resistant and received oral 4.5 mg/m\^2 once daily.

Part 2, ALK-resistant: DS-2248 4.5 mg/m^2

Participants who were ALK treatment naive and received oral 4.5 mg/m\^2 once daily.

Part 2, ALK-naive: DS-2248 4.5 mg/m^2

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

United States

Region of Enrollment

Demographics and baseline characteristics were assessed in the Enrolled Analysis Set.

Contact for Clinical Trial Information

Objective response rate was assessed in the Full Analysis Set.

Summary of Objective Response Rate Following Oral Administration of DS-2248 in Participants With Advanced Solid Tumors

Confirmed CR

Confirmed PR

Stable disease

Progressive disease

Non-evaluable

Best overall response was assessed in the Full Analysis Set.

Summary of Best Overall Response Rate Following Oral Administration of DS-2248 in Participants With Advanced Solid Tumors

Disease control rate was assessed in the Full Analysis Set.

Summary of Disease Control Rate Following Oral Administration of DS-2248 in Participants With Advanced Solid Tumors

Duration of stable disease was assessed in participants in which data were available in the Full Analysis Set.

Duration of Stable Disease Following Oral Administration of DS-2248 in Participants With Advanced Solid Tumors

Progression-free survival was assessed in the Full Analysis Set.

Summary of Progression-free Survival Following Oral Administration of DS-2248 in Participants With Advanced Solid Tumors

Pharmacokinetic parameters were assessed in the Pharmacokinetic Analysis Set for which data were available.

Summary of Pharmacokinetic Parameter Area Under the Concentration Versus Time Curve From Zero to Infinity Following Oral Administration of DS-2248 in Participants With Advanced Solid Tumors

Summary of Pharmacokinetic Parameter Maximum Concentration Following Oral Administration of DS-2248 in Participants With Advanced Solid Tumors

Summary of Pharmacokinetic Parameter Time at Maximum Concentration Following Oral Administration of DS-2248 in Participants With Advanced Solid Tumors

Summary of Pharmacokinetic Parameter Terminal Half-life Following Oral Administration of DS-2248 in Participants With Advanced Solid Tumors

Summary of Pharmacokinetic Parameter Total Body Clearance Following Oral Administration of DS-2248 in Participants With Advanced Solid Tumors

Drug-related TEAEs

Blood and Lymphatic Disorders

Anaemia

Thrombocytopenia

Lymphopenia

Cardiac Disorders

Tachycardia

Eye Disorders

Retinal haemorrhage

Dry eye

Photopsia

Vision blurred

Vitreous floaters

Gastrointestinal Disorders

Abdominal distension

Anorectal discomfort

Constipation

Diarrhoea

Dyspepsia

Flatulence

Nausea

Vomiting

Abdominal pain

Gastrooesophageal reflux disease

Paraesthesia oral

General Disorders & Administration Site Conditions

Fatigue

Oedema peripheral

Irritability

Immune System Disorders

Hypersensitivity

Investigations

Alanine aminotransferase increase

Aspartate aminotransferase increased

Blood alkaline phosphatase increased

Blood creatinine increased

Blood urea increased

Blood uric acid increased

Blood phosphorus increased

Weight decreased

Weight increased

Metabolism and Nutrition Disorders

Decreased appetite

Dehydration

Hyperglycaemia

Hyperphosphataemia

Hyperuricaemia

Hypoalbuminaemia

Hypokalaemia

Musculoskeletal and Connective Tissue Disorders

Arthralgia

Muscular weakness

Musculoskeletal pain

Myalgia

Nervous System Disorders

Dizziness

Dysgeusia

Headache

Nystagmus

Restless legs syndrome

Renal and Urinary Disorders

Proteinuria

Renal failure acute

Respiratory, Thoracic, and Mediastinal Disorders

Dyspnoea

Reproductive System and Breast Disorders

Breast tenderness

Skin and Subcutaneous Tissue Disorders

Dry skin

Hyperhidrosis

Onychoclasis

Pruritus

All participants who received oral DS-2248 in Part 1.

Total - Part 1

All participants who received oral DS-2248 in Part 2.

Total - Part 2

Treatment-emergent adverse events were assessed in the Safety Analysis Set.

Summary of Drug Related Treatment Emergent Adverse Events Following Oral Administration of DS-2248 in Participants With Advanced Solid Tumors

Part 1

Part 2

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Study of DS-2248 in Participants With Advanced Solid Tumors	NCT01288430	Solid Tumors Non-small Cell ...	DS-2248	18 Years -	Daiichi Sankyo
A Study of DS-2248 in Participants With Advanced Solid Tumors	NCT01288430	Solid Tumors Non-small Cell ...	DS-2248	18 Years -	Daiichi Sankyo
A Study of DS-2248 in Participants With Advanced Solid Tumors	NCT01288430	Solid Tumors Non-small Cell ...	DS-2248	18 Years -	Daiichi Sankyo

Spots Global Cancer Trial Database for tyrosine kinase inhibitor acquired resistance