LCL161 Plus Topotecan for Patients With Relapsed/Refractory Small Cell Lung Cancer and Select Gynecologic Malignancies

NCT02649673 | Terminated Phase 1

• 1 other identifier: SCRI REFMAL 314
• Study Type: interventional
• Target: 34
• Locations: 1 country
• Sites: 3

Brief Summary

This trial will investigate the combination of two anti-cancer agents to treat patients with relapsed/refractory small cell lung cancer (SCLC) and ovarian cancers. Oral topotecan has US FDA approval for treating select gynecological cancers and SCLC. LCL161 is an investigational product that has been shown in clinical trials to work together with other anti-cancer agents. In this trial, investigators will determine the optimal dose of LCL161 and topotecan to administer to patients with relapsed/refractory SCLC and ovarian cancers, and examine the safety profile of the drug combination.

Conditions

Small Cell Lung Cancer; Ovarian Cancer

Keywords

lung carcinoma; topotecan; Hycamtin; ovarian neoplasms; LCL161; IAP inhibitors

Outcome Measures

Primary Outcomes (1)

• The incidence of dose-limiting toxicities (DLTs) as a measure of safety and tolerability

  The maximum tolerated dose (MTD) of the LCL161/topotecan combination is defined as the highest dose that results in dose-limiting toxicities (DLTs) for 2 of 6 patients during the first 21 days (1 cycle) of treatment, assessed using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.

  21 days (one cycle)

Secondary Outcomes (2)

• The incidence of acute and chronic treatment-emergent adverse events to further assess safety of the regimen

  weekly for first 3 weeks then every 3 weeks thereafter, projected 6 months.

• Best overall response

  every 6 weeks, projected 6 months

Study Arms (1)

LCL161+topotecan+Pegylated GCSF (PEG-GCSF)

EXPERIMENTAL

Dose Escalation: Groups of 3-6 patients per dose level (DL) will initiate treatment in escalating doses until the maximum tolerated dose (MTD) is reached. MTD is defined as the highest combination of doses that results in dose-limiting toxicities for 2 of 6 patients per dosing group. * LCL161: orally, on Days 1, 8, 15 of each 21-day cycle. Maximum dose not to exceed 1200 mg/week. * topotecan: orally, for first 5 days of each 21-day cycle. Maximum dose not to exceed 2.3 mg/m2 per day. * Pegylated GCSF (PEG-GCSF) on-body injector (OBI) or daily GCSF (e.g. filgrastim) will be given according to institutional policy after Day 5 of topotecan. Because patients treated with topotecan are at high risk of developing febrile neutropenia, GCSF will be given in the prophylactic setting. Dose Expansion: 24 additional patients will be treated at the MTD in 2 cohorts (SCLC-12 patients; ovarian cancer-12 patients)

Drug: LCL161; Drug: Topotecan; Drug: Pegylated GCSF (PEG-GCSF)

Interventions

LCL161 DRUG

LCL161+topotecan+Pegylated GCSF (PEG-GCSF)

Topotecan DRUG

Topotecan will also be administered orally. Patients in DL 1 will receive topotecan at 1.8 mg/m2 per day for the first 5 days of each 21-day cycle. Patients in DL 2 will receive topotecan at 2.3 mg/m2 per day for the first 5 days of each 21-day cycle. The maximum dose for topotecan will not exceed 2.3 mg/m2 per day in this study.

Also known as: Hycamtin®

LCL161+topotecan+Pegylated GCSF (PEG-GCSF)

Pegylated GCSF (PEG-GCSF) DRUG

Pegylated GCSF (PEG-GCSF) (e.g. pegfilgrastim) on-body injector (OBI) or daily GCSF (e.g. filgrastim) will be given according to institutional policy after Day 5 of topotecan. Because patients treated with topotecan are at high risk of developing febrile neutropenia, GCSF will be given in the prophylactic setting.

Also known as: pegfilgrastim

LCL161+topotecan+Pegylated GCSF (PEG-GCSF)

Eligibility Criteria

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

You may qualify if:

• Dose Escalation Portion: Must have histological diagnosis of relapsed/refractory SCLC or gynecological malignancy for which topotecan would be indicated.
• Dose Expansion Portion: Must have histological diagnosis of relapsed/refractory SCLC or ovarian cancer for which topotecan would be indicated.
• Patients must have evidence of recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer and must have previously received a platinum- / taxane-based chemotherapy regimen unless contraindicated. Only patients with platinum-resistant disease (recurrence \< 6 months after platinum-based chemotherapy) are eligible.
• Patients with SCLC must have received platinum-based chemotherapy unless contraindicated.
• Patients must provide written informed consent prior to any screening procedures.
• Measurable or non-measurable (but evaluable) disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (Eisenhauer et al. 2009)
• Required baseline laboratory status:
• Hemoglobin ≥90 g/L (9 g/dL)
• Platelets ≥100 x 109/L (100,000/mm3)
• Absolute neutrophil count (ANC) ≥1.5 x 109/L (1500/mm3)
• Serum total bilirubin ≤1.5 x the upper limit of normal (ULN) (in patients with known Gilbert Syndrome, a total bilirubin ≤3.0 x ULN, with direct bilirubin ≤1.5 x ULN)
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x the ULN, except for patients with tumor involvement of the liver who must have ALT and AST ≤5 x ULN
• Creatinine clearance ≥ 50 mL/min, (measured by Cockcroft-Gault method):
• Aged ≥18 years
• Ability to swallow and retain oral medication

You may not qualify if:

• Patients with brain metastases may be enrolled if radiation and/or surgery have been completed and follow-up evaluation by computed tomography (CT) or magnetic resonance imaging (MRI) after 1 month demonstrates stable disease (SD), and the patient does not require corticosteroids or enzyme-inducing anti-epileptic medications for central nervous system disease. Patients with SCLC should have brain imaging performed within the last 2 months prior to study entry.
• More than 3 prior cytotoxic chemotherapy regimens given in the metastatic setting.
• Second-line ovarian cancer patients that are platinum-sensitive.
• Most recent chemotherapy ≤21 days and unresolved toxicities National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v4.03 Grade ≥2 (except alopecia)
• Use of an investigational drug ≤21 days or 5 half-lives (whichever is shorter) prior to the first dose of LCL161. For study drugs for which 5 half-lives is ≤21 days, a minimum of 14 days between termination of the study drug and administration of LCL161 is required
• Impairment of gastrointestinal function or gastrointestinal disease that may alter absorption of oral medications
• Major surgery ≤3 weeks or minor surgical procedures ≤7 days prior to study entry. No waiting is required following port-a-cath placement.
• Patients who are currently receiving chronic (\>14 days) treatment with corticosteroids at a dose ≥10 mg of prednisone (or its glucocorticoid equivalent) per day, or any other chronic immunosuppressive treatment that cannot be discontinued prior to starting study drug
• Patients who are currently receiving treatment with agents that are metabolized solely through cytochrome P450 (CYP) 3A4/5 (CYP3A4/5) and have a narrow therapeutic index or are strong CYP2C8 inhibitors; or are receiving treatment with agents that carry a risk for QT prolongation and are CYP3A substrates. Caution should be used in patients taking other CYP2C8- or CYP3A4/5-interacting agents.
• New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities (see Appendix B), prolongation of the QTc interval to \>450 msec for males or \>470 msec for females on baseline electrocardiogram (ECG) per institutional standard or any of the following:
• History or presence of ventricular tachyarrhythmia
• Clinically significant resting bradycardia (\<50 bpm)
• Angina pectoris or acute myocardial infarction ≤3 months prior to starting study drug
• Other clinically significant heart disease (e.g., symptomatic congestive heart failure, uncontrolled arrhythmia or hypertension)
• Patients who are pregnant (positive beta-human chorionic gonadotropin \[β-HCG\]) or breastfeeding.

Sponsors & Collaborators

• SCRI Development Innovations, LLC: lead
• Novartis Pharmaceuticals: collaborator

Study Sites (3)

Florida Cancer Specialists-Sarasota

Sarasota, Florida, 34232, United States

Location

Oklahoma University Health Science Center/Stephenson Cancer Center

Oklahoma City, Oklahoma, 73104, United States

Location

Tennessee Oncology PLLC

Nashville, Tennessee, 37203, United States

Location

Related Publications (1)

• Johnson ML, Patel MR, Aljumaily R, Jones SF, Burris Iii HA, Spigel DR. A Phase Ib Dose-Escalation Study of LCL161 Plus Oral Topotecan for Patients With Relapsed/Refractory Small Cell Lung Cancer and Select Gynecologic Malignancies. Oncologist. 2023 Jul 5;28(7):640-e559. doi: 10.1093/oncolo/oyad029.

  PMID: 37129455 DERIVED

MeSH Terms

Conditions

Small Cell Lung Carcinoma; Ovarian Neoplasms; Lung Neoplasms

Interventions

LCL161; Topotecan; pegfilgrastim

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Endocrine Gland Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Genital Diseases; Endocrine System Diseases; Gonadal Disorders

Intervention Hierarchy (Ancestors)

Camptothecin; Alkaloids; Heterocyclic Compounds

Study Officials

• Melissa Johnson, MD

  SCRI Development Innovations, LLC

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 5, 2016
• First Posted: January 7, 2016
• Study Start: March 23, 2016
• Primary Completion: July 30, 2021
• Study Completion: July 30, 2021
• Last Updated: December 5, 2023

Record last verified: 2022-06

Locations

US (3)