RO4929097 and Erlotinib Hydrochloride in Treating Patients With Stage IV or Recurrent Non-small Cell Lung Cancer

NCT01193881 | Terminated Phase 1

• 7 other identifiers: NCI-2010-019752009-07698508N01CM00039N01CM62202P30CA016672U01CA062461
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

Brief Summary

This phase I trial studies the side effects and best dose of gamma-secretase/Notch signalling pathway inhibitor RO4929097 (RO4929097) and erlotinib hydrochloride when given together in treating patients with non-small cell lung cancer that is stage IV or has come back. RO4929097 and erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Conditions

Recurrent Non-Small Cell Lung Carcinoma; Stage IV Non-Small Cell Lung Cancer

Outcome Measures

Primary Outcomes (6)

• Incidence of adverse events assessed using NCI CTCAE version 4.0 (Dose escalation phase)

  Within 30 days of last drug dose

• Maximum-tolerated dose of RO4929097 and erlotinib hydrochloride defined as the highest dose tested causing dose limiting toxicity in < 2/6 patients assessed using National Cancer Institute (NCI) CTCAE version 4.0 (Dose escalation phase)

  At least 3 weeks after day 1 of course 1

• Percentage of change in expression of Notch and other tumor and blood biomarkers (Expansion cohort)

  The differences before and after treatment will be assessed using a paired-t test on the log-transformed tumor sizes and a Wilcoxon signed-rank test.

  Baseline to 6 weeks

• Percentage of tumor shrinkage (Expansion cohort)

  Will be correlated with response and baseline expression of biomarkers. The differences before and after treatment will be assessed using a paired-t test on the log-transformed tumor sizes and a Wilcoxon signed-rank test.

  Up to 6 weeks

• Response rate by RECIST 1.1 (Expansion cohort)

  Up to 12 weeks

• Time to progression (Expansion cohort)

  Will be correlated with baseline expression or biomarkers.

  Up to 12 weeks

Other Outcomes (4)

• Efficacy of this combination in unselected patients and in patients with intrinsic or acquired erlotinib resistance (Dose escalation phase)

  Up to 12 weeks

• Host Notch pathway gene polymorphisms

  Up to 6 weeks

• Pre-therapy tumor expression of Notch and other tumor and blood biomarkers (Dose escalation phase)

  Baseline

Study Arms (1)

Treatment (erlotinib, RO4929097)

EXPERIMENTAL

Patients receive erlotinib hydrochloride PO QD on days 1-21 and gamma-secretase/Notch signalling pathway inhibitor RO4929097 PO QD on days 1-3, 8-10, and 15-17. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Drug: Erlotinib Hydrochloride; Drug: Gamma-Secretase Inhibitor RO4929097; Other: Laboratory Biomarker Analysis; Other: Pharmacological Study

Interventions

Erlotinib Hydrochloride DRUG

Given PO

Also known as: Cp-358,774, OSI-774, Tarceva

Treatment (erlotinib, RO4929097)

Gamma-Secretase Inhibitor RO4929097 DRUG

Given PO

Also known as: RO4929097

Treatment (erlotinib, RO4929097)

Laboratory Biomarker Analysis OTHER

Correlative studies

Treatment (erlotinib, RO4929097)

Pharmacological Study OTHER

Correlative studies

Treatment (erlotinib, RO4929097)

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:
• Patients must have histologically or cytologically confirmed diagnosis of incurable NSCLC
• Preference will be given to patients with NSCLC who have been treated with erlotinib, and have either responded initially and then experienced subsequent growth in one or more tumor deposits while continuing erlotinib (acquired resistance) or patients who have been treated with erlotinib and failed to demonstrate any response to it (intrinsic resistance)
• Expansion cohort: patients must satisfy each of the following criteria:
• Histologically or cytologically confirmed non-small cell lung cancer that is incurable (stage IV or recurrent)
• Patients must not have received prior anti-EGFR therapy
• Patients on both the dose escalation portion of the study and in the Expansion Cohort portion must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as \>= 10 mm with computed tomography (CT) scan with cuts at 2.5 or 5 mm
• Patients on both portions of the study must have tumor amenable to core biopsy (or to incisional, excisional, or punch biopsy) for research purposes; the collaborating interventional radiologists will make the determination whether or not the patient has a tumor amenable to biopsy and whether or not the patient is medically an appropriate candidate for tumor biopsy
• Any prior anticancer systemic therapy or radiotherapy must have been completed at least 4 weeks prior to initiation of therapy on this study; (Exception: patients may be entered within 2 weeks of radiotherapy if the radiotherapy was restricted to femur below the trochanter, humerus or more distal limb areas)
• Dose escalation portion:
• Unlimited prior therapy is permitted (including prior anti-EGFR therapy), with the exception that patients who have received prior therapy with a gamma-secretase inhibitor are not eligible
• Prior therapy is not required
• Preference will be given to NSCLC patients who have been treated with erlotinib with evidence of acquired or intrinsic resistance to erlotinib
• Expansion cohort:
• Patients may have received an unlimited number of prior systemic regimens for NSCLC (as adjuvant therapy, as therapy for locally advanced disease or as therapy for advanced disease) provided they have not received prior anti-EGFR therapy (small molecule or antibody, etc) or prior gamma-secretase inhibitors

You may not qualify if:

• Patients may not have received other systemic therapy or radiotherapy for their cancer within the previous 4 weeks prior to planned first day of therapy on this trial; (Exception: patients may be entered within 2 weeks of radiotherapy if the radiotherapy was restricted to distal limbs such as femur below the trochanter, humerus or more distal limb areas; in addition, patients in the dose escalation portion who have previously received erlotinib may start therapy on this trial as early as 1 week after stopping prior erlotinib provided all other study entry criteria are met)
• Patients on the expansion cohort may not have received prior anti-EGFR therapy (small molecule tyrosine kinase inhibitor \[TKI\] or antibody); (Note: this in contrast to the dose escalation portion of the study in which patients with prior anti-EGFR therapy will be eligible)
• Patients may not be receiving any other investigational agents
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to RO4929097, OSI-774 or other agents used in the study
• Patients taking medications with narrow therapeutic indices that are metabolized by cytochrome P450 (CYP450), including warfarin sodium (Coumadin®) are ineligible
• Caution should be exercised when dosing RO4929097 concurrently with CYP3A4 substrates, inducers, and/or inhibitors; furthermore, patients who are taking concurrent medications (other than erlotinib) that are strong inducers/inhibitors or substrates of CYP3A4 should be switched to alternative medications; if such patients cannot be switched to alternative medications, they will be ineligible to participate in this study; if a patient is taking a strong CYP3A4 inhibitor/inducer other than the 2 study drugs, they should be switched to an alternative drug
• Patients with malabsorption syndrome or other condition that would interfere with intestinal absorption
• Diarrhea \> grade 1 despite appropriate therapy
• Patients who are known to be serologically positive for hepatitis A, B or C are ineligible
• Patients with \> grade 1 (by Common Terminology Criteria for Adverse Events \[CTCAE\] criteria) hyponatremia or hypocalcemia (based on measurement of ionized calcium) despite appropriate medical management are excluded from this study, as are patients with hypophosphatemia (serum phosphate below the lower limit of normal for the institution), hypomagnesemia, (serum magnesium below the lower limit of normal), hypokalemia, or hyperkalemia (serum potassium outside normal limits) despite appropriate medical management
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring systemic therapy (with antibiotics, antiviral or antifungal agents), symptomatic congestive heart failure, unstable angina pectoris, angina at rest, a history of torsades de pointes, potentially life-threatening cardiac arrhythmias (patients are permitted to have chronic, stable atrial fibrillation, premature atrial or ventricular contractions, sinus tachycardia, provided the rate is controlled at \< 115 per minute, and sinus bradycardia, provided the rate is \> 50 per minute), myocardial infarction within the previous 3 months, or psychiatric illness/social situations that would limit compliance with study requirements
• Pregnant women are excluded from this study
• Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible
• Cardiovascular: baseline corrected QT interval using Fridericia's formula (QTcF) \> 450 msec (male) or QTcF \> 470 msec (female)
• Patients requiring drugs that are known to cause Torsades de pointes and/or prolonged corrected QT (QTc) intervals are excluded; patients requiring drugs with a possible but unproven association with Torsades de pointes and/or QTc prolongation may be eligible, but will require additional electrocardiogram assessments, as outlined

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

M D Anderson Cancer Center

Houston, Texas, 77030, United States

Location

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Interventions

Erlotinib Hydrochloride; 2,2-dimethyl-N-(6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-N'-(2,2,3,3,3-pentafluoropropyl)malonamide

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Quinazolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Don Gibbons

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

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

Study Record Dates

• First Submitted: September 1, 2010
• First Posted: September 2, 2010
• Study Start: August 1, 2010
• Primary Completion: August 1, 2015
• Study Completion: August 1, 2015
• Last Updated: September 29, 2015

Record last verified: 2015-09

Locations

US (1)