Phase Ib/II Study of M3814 With Etoposide and Cisplatin in Small Cell Lung Cancer (SCLC) Extensive Disease (ED)

Phase 1TerminatedNCT03116971

EMD Serono Research & Development Institute, Inc.2 enrolled

Overview

M3814 is an investigational drug under evaluation for treatment of lung cancer. The purpose of the study was to assess the Safety and Efficacy of M3814 in combination with chemotherapy with SCLC ED.

The study was intended to be a phase I/II trial, but the study never moved forward to Phase II due to recruitment challenges.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

Conditions

Small Cell Lung Cancer

Interventions

M3814DRUG

Participants received M3814 PiC or hot melt extrusion (HME) tablet orally once daily in combination with etoposide (intravenously) and cisplatin for 6 cycles with each cycle lasting 3 weeks (21 days).

CisplatinDRUG

Cisplatin 75 milligram per square meter (mg/m\^2) was administered over a 60-minute intravenous infusion on Day 1.

EtoposideDRUG

Etoposide 100 mg/m\^2 over a 60 minute IV infusion on Days 1-3 was administered for 6 cycles with each cycle lasting 3 weeks (21 days).

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: To be eligible for the study (Phase Ib and Phase II) the participant must fulfill all of the following criteria: * Male or female participants at least 18 years of age * Histological or cytological diagnosis of SCLC * Extensive disease (ie, disease beyond ipsilateral hemithorax, which may include malignant pleural or pericardial effusion or hematogenous metastases \[Tany, Nany, M1a/b; T3-T4, Nany, M0, due to multiple lung nodules or extent of disease that precludes a tolerable radiation field, as judged by the Investigator\]) * Participants eligible for first line platinum-based chemotherapy * Measurable or evaluable disease according to RECIST v1.1 * Eastern Cooperative Oncology Group performance status (ECOG PS) less than equals to (\<=) 2 * Life expectancy of greater than equals to (≥) 3 months * Female participants of childbearing potential and male participants with female partners of childbearing potential must be willing to avoid pregnancy Note: Other protocol defined criteria could apply. Exclusion Criteria: Participants are not eligible for the study if they fulfill any of the following exclusion criteria: * Prior anticancer therapy for extensive disease (ED) SCLC including experimental agents. * Concurrent use of other anticancer therapy including any investigational agent within 28 days prior to the first dose of the investigational drug M3814. * Extensive prior radiotherapy (RT) on more than 30% of bone marrow reserves (by Investigator judgment) * Prior bone marrow/stem cell transplantation within 5 years before study start (Phase II only) * Major surgical intervention within 28 days prior to the first dose of investigational drug administration. Intervention(s) to establish the diagnosis for SCLC is permitted within 28 days as long as participants are cleared by the medical and surgical teams. * Poor vital organ functions defined as: * Bone marrow impairment as evidenced by hemoglobin less than (\<) 9.0 gram per deci liter (g/dL) (5.7 micromole per liter (μmol/L)), absolute neutrophil count \< 1.5 × 109/L, platelets \< 100 × 109/L * Renal impairment as evidenced by calculated creatinine clearance \< 60 mL/minutes (min) (according to the Cockcroft-Gault formula) * Liver function abnormality as defined by total bilirubin greater than (\>) 1.5 × upper limit of normal (ULN) or aspartate aminotransferase (AST)/alanine aminotransferase (ALT) \> 2.5 × ULN (participants with liver involvement: a maximum of AST/ALT 5 × ULN) * Contraindication to the use of etoposide or cisplatin * Participants currently receiving (or unable to stop using prior to receiving the first dose of investigational drug) medications or herbal supplements known to be potent inhibitors of cytochrome P450 (CYP) 3A and CYP2C19 (unless treatment can be discontinued at least 1 week prior to receiving the first dose of investigational drug) or potent inducers of CYP3A and CYP2C19 (unless treatment can be discontinued at least 3 weeks prior to receiving the first dose of investigational drug). Note: Other protocol defined criteria could apply.

Locations (80)

Outcomes

Primary Outcomes

Phase Ib: Number of Subjects Experienced Any Dose-Limiting Toxicity (DLT) over the DLT period.

Time frame: up to 21 days

Phase Ib: Determination of Recommended Phase II dose (RP2D) of Escalating Dose of M3814 in Combination With Cisplatin and Etoposide for the Phase II Part of the Study

Time frame: up to 11 months

Phase II: Progression Free Survival (PFS) as Assessed by the Investigator according to RECIST v1.1

PFS time will be evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. The PFS time is defined as the duration from randomization to either first observation of progressive disease (PD) or occurrence of death due to any cause.

Time frame: Time from randomization to first assessment of disease progression or death, whichever is earlier, assessed up to 24 months

Secondary Outcomes

Phase Ib: Number of Subjects with of Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Deaths

An Adverse Event (AE) is defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. A SAE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect.

Time frame: From the first dose of study drug treatment up to 30 days after the last dose of study drug treatment

Phase Ib: Number of Subjects with Abnormal Laboratory Values, Abnormal Vital Signs and Abnormal Electrocardiograms (ECGs)

Subjects will be analyzed for vital signs (eg, body temperature, respiratory rate, heart rate, and blood pressure), laboratory parameters and 12-lead ECG recorded at baseline and after administration of M3814. Number of subjects with abnormal values for laboratory values, vital signs and electrocardiograms (ECGs) will be reported.

Data from ClinicalTrials.gov

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Research site

Mesa, Arizona, United States

Research site 1

Santa Rosa, California, United States

Research site

Santa Rosa, California, United States

Research site

Whittier, California, United States

Research site

Danbury, Connecticut, United States

Research site

Norwalk, Connecticut, United States

Research site

Columbus, Georgia, United States

Research site

Newnan, Georgia, United States

Research site

Topeka, Kansas, United States

Research site

Ashland, Kentucky, United States

...and 70 more locations

Time frame: From the first dose of study drug treatment up to 30 days after the last dose of study drug treatment

Phase Ib: Change in Eastern Cooperative Oncology Group performance status (ECOG PS)

Time frame: From the first dose of study drug treatment up to 30 days after the last dose of study drug treatment

Phase Ib: Percentage of Subjects with Objective Response (OR) According to RECIST v1.1

The Objective Response Rate (ORR) is defined as the percentage of subjects whose Best objective response (BOR) is either complete response (CR) or partial response (PR). The ORR will be derived from the BOR according to response evaluation criteria in solid tumors (RECIST) v1.1 as assessed by the Investigator.

Time frame: Post randomization with period tumor evaluations until disease progression or subject withdrawal of consent, irrespective of treatment discontinuation or initiation of another therapy, assessed up to 11 months

Phase Ib: Duration of Response (DoR) According to RECIST v1.1

The DoR applies only to subjects whose BOR is either CR or PR. The duration is measured from the first documented response (CR or PR, whichever is first recorded) until the first assessment of Progressive Disease (PD).The DoR will be derived from the BOR according to RECIST v1.1 as assessed by the Investigator.

Time frame: First documented complete response or partial response, whichever is first recorded until the first assessment of disease progression, assessed up to 11 months

Phase Ib: Percentage of Subjects With Disease Control

Percentage of subjects with disease control as assessed by best overall response of either CR, PR or Stable Disease (SD) will be reported.

Time frame: First documented complete response or partial response, whichever is first recorded until the first assessment of disease progression, assessed up to 11 months

Phase Ib: Progression Free Survival (PFS) According to RECIST v1.1

The PFS time is defined as the duration from randomization to either first observation of progressive disease (PD) or occurrence of death due to any cause. The PFS will be derived according to RECIST v1.1 as assessed by the Investigator.

Time frame: Time from randomization to first assessment of disease progression or death, whichever is earlier, assessed up to 11 months

Phase Ib: Overall Survival (OS)

The OS time is defined as the date from randomization to death due to any cause.

Time frame: Time from randomization to death due to any cause, assessed up to 11 months

Phase Ib: Area under the concentration-time curve from 0 to 4 hours (AUC 0-4), 0 to 24 hours (AUC 0-24) for M3814, Cisplatin and Etoposide

Time frame: Day (D) -1, Cycle (C) 1D1, C2D1: Pre-dose, 0.5, 1, 1.5, 2, 3, 3.5, 4, 6 and 8 hours (hrs) post dose; C1D2 Pre-dose, C1D3 Pre-dose, C1D8 Pre-dose, C1D15 Pre-dose and 2 hrs post dose, C2D3 Pre-dose, C3D1 Pre-dose and 3.5 hrs post dose

Phase Ib: Area Under the Concentration-Time Curve From Time 0 to the Last Quantifiable Concentration (AUC 0-t ) for M3814, Cisplatin and Etoposide

Time frame: Day (D) -1, Cycle (C) 1D1, C2D1: Pre-dose, 0.5, 1, 1.5, 2, 3, 3.5 (excluding D-1), 4, 6 and 8 hours (hrs) post dose; C1D2 Pre-dose, C1D3 Pre-dose, C1D8 Pre-dose, C1D15 Pre-dose and 2 hrs post dose, C2D3 Pre-dose

Phase Ib: Maximum Observed Plasma Concentration (Cmax) for M3814, Cisplatin and Etoposide

Time frame: Day (D) -1, C1D1, C2D1: Pre-dose, 0.5, 1, 1.5, 2, 3, 3.5 (excluding D-1), 4, 6 and 8 hours (hrs) post-dose; C1D2 Pre-dose, C1D3 Pre-dose, C1D8 Pre-dose, C1D15 Pre-dose and 2 hrs post-dose, C2D3 Pre-dose

Phase Ib: Time to Reach Maximum Plasma Concentration (Tmax) for M3814, Cisplatin and Etoposide

Phase Ib: Apparent Terminal Half-life (t1/2) for M3814

Time frame: C1D1: Pre-dose, 0.5, 1, 1.5, 2, 3, 3.5, 4, 6 and 8 hours (hrs) post-dose

Phase Ib: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of M3814

Time frame: C1D1: Pre-dose, 0.5, 1, 1.5, 2, 3, 3.5, 4, 6 and 8 hours (hrs) post-dose

Phase Ib: Total Body Clearance From Plasma Following Extravascular Administration (CL/f) of M3814

Phase Ib: Intravenous (IV) Clearance (CL) of Cisplatin and Etoposide

Time frame: Day (D) -1, C1D1, C2D1: Pre-dose, 0.5, 1, 1.5, 2, 3, 3.5 (excluding D-1), 4, 6 and 8 hr post dose; C1D2 Pre-dose, C1D3 Pre-dose, C1D8 Pre-dose, C1D15 Pre-dose and 2 hrs post dose, C2D3 Pre-dose

Phase Ib: Apparent Volume of Distribution Following Extravascular Administration (Vz/f) of M3814

Time frame: Day (D) -1, C1D1, C2D1: Pre-dose, 0.5, 1, 1.5, 2, 3, 3.5 (excluding D-1), 4, 6 and 8 hours (hrs) post dose; C1D2 Pre-dose, C1D3 Pre-dose, C1D8 Pre-dose, C1D15 Pre-dose and 2 hrs post dose, C2D3 Pre-dose

Phase Ib: Apparent Volume of Distribution (Vz) of Cisplatin and Etoposide

Phase Ib: Terminal rate constant (λz) for M3814, Cisplatin and Etoposide

Phase Ib: Changes in Cmax for M3814 Between Day -1 and C2D1

Time frame: Day (D) -1, Cycle (C) 2D1: Pre-dose, 0.5, 1, 1.5, 2, 3, 3.5 (excluding D-1), 4, 6 and 8 hours (hrs) post dose

Phase Ib: Changes in AUC for M3814 Between Day -1 and C2D1

Time frame: Day (D) -1, Cycle (C) 2D1: Pre-dose, 0.5, 1, 1.5, 2, 3, 3.5 (excluding D-1), 4, 6 and 8 hours (hrs) post dose

Phase Ib: Changes in AUC for Etoposide From C1D1 to C1D2, C1D3, and C2D1 (for the first 2 dose levels), or From C1D1 to C2D1 (other dose levels)

Time frame: Day (D) -1, Cycle (C) 1D1, C2D1: Pre-dose, 0.5, 1, 1.5, 2, 3, 3.5 (excluding D-1), 4, 6 and 8 hours (hrs) post dose

Phase Ib: Changes in Cmax for Etoposide From C1D1 and C2D1

Time frame: Cycle (C) 1D1, C2D1: Pre-dose, 0.5, 1, 1.5, 2, 3, 3.5 (excluding D-1), 4, 6 and 8 hours (hrs) post dose

Phase Ib: Changes in AUC for Cisplatin From C1D1 to C1D2, C1D3, and C2D1 (for the first 2 dose levels), or From C1D1 to C2D1 (other dose levels)

Time frame: Day (D) -1, Cycle (C) 1D1, C2D1: Pre-dose, 0.5, 1, 1.5, 2, 3, 3.5 (excluding D-1), 4, 6 and 8 hours (hrs) post dose

Phase Ib: Changes in Cmax for Cisplatin From C1D1 and C2D1

Time frame: Cycle (C) 1D1, C2D1: Pre-dose, 0.5, 1, 1.5, 2, 3, 3.5 (excluding D-1), 4, 6 and 8 hours (hrs) post dose

Phase II: Overall Survival (OS)

Time frame: Time from randomization to death due to any cause, assessed up to 24 months

Phase II: Percentage of Subjects with Objective Response (OR) According to RECIST v1.1

The Objective Response Rate (ORR) is defined as the proportion of subjects whose Best objective response (BOR) is either complete response (CR) or partial response (PR). The ORR will be derived from the BOR according to response evaluation criteria in solid tumors (RECIST) Version 1.1 as assessed by the Investigator.

Time frame: Post randomization every 6 weeks up to Week 54 and then every 12 weeks until disease progression or subject withdrawal of consent, irrespective of treatment discontinuation or initiation of another therapy., assessed up to 24 months

Phase II: Duration of Response (DoR) According to RECIST v1.1

Time frame: First documented complete response or partial response, whichever is first recorded until the first assessment of disease progression, assessed up to 24 months

Phase II: Percentage of Subjects With Disease Control

Percentage of subjects with disease control as assessed by best overall response of either CR, PR or Stable Disease (SD) will be reported.

Time frame: First documented complete response or partial response, whichever is first recorded until the first assessment of disease progression, assessed up to 24 months

Phase II: Percentage of Subjects Who Received Prophylactic Cranial Irradiation (PCI) and/or Thorax Irradiation After 6 Cycles of Treatment

Time frame: After 6 Cycles of treatment, assessed up to 24 months

Phase II: Tumor shrinkage From Baseline in target lesions

Phase II: Number of subjects with of Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Deaths

An Adverse Event (AE) is defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. A Serious AE (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect.

Time frame: From the first dose of study drug treatment up to 30 days after the last dose of study drug treatment

Phase II: Number of Subjects with Abnormal Laboratory Values, Abnormal Vital Signs and Abnormal Electrocardiograms (ECGs)

Time frame: From the first dose of study drug treatment up to 30 days after the last dose of study drug treatment

Phase II: Change in Eastern Cooperative Oncology Group performance status (ECOG PS)

Time frame: From the first dose of study drug treatment up to 30 days after the last dose of study drug treatment

Phase II: Primary Health-Related Quality of Life (HRQoL) Based on Time to Definitive Deterioration (TUDD) as Assessed Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30)

Time frame: Screening; Post randomization every 6 weeks up to Week 54 and then every 12 weeks until disease progression or subject withdrawal of consent, irrespective of treatment discontinuation or initiation of another therapy., assessed up to 24 months

Phase II: Primary HRQoL based on TUDD Assessed Using EORTC Quality of Life Questionnaire-Lung Cancer 13 (QLQ-LC13)

Phase II: Primary HRQoL based on TUDD Assessed Using European Quality of Life 5- dimensions questionnaire (EQ-5D)

Phase II: Area under the concentration-time curve from 0 to 24 hours (AUC 0-24) for M3814, Cisplatin and Etoposide