RO4929097 in Treating Patients With Advanced Non-Small Cell Lung Cancer Who Have Recently Completed Treatment With Front-Line Chemotherapy

NCT01193868 | Terminated Phase 2 Results

• 7 other identifiers: NCI-2010-01989CDR0000684242MDA-2009-06492009-06498506N01CM00039P30CA016672
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

Brief Summary

This phase II trial is studying how well RO4929097 works in treating patients with advanced non-small cell lung cancer who have recently completed treatment with front-line chemotherapy. RO4929097 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Conditions

Recurrent Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IV Non-small Cell Lung Cancer

Outcome Measures

Primary Outcomes (2)

• Response Rate by Response Evaluation Criteria in Solid Tumors (RECIST)

  Percentage of participants with response per RECIST version 1.1: Complete Response (CR):Disappearance all target lesions. Any pathological lymph nodes with reduction in short axis to \<10 mm. Partial Response (PR): At least 30% decrease in sum of diameters of target lesions, reference baseline sum diameters. Progressive Disease (PD): At least 20% increase in sum of diameters of target lesions, reference smallest sum on study (includes baseline sum if that is smallest on study). In addition to relative increase of 20%, sum must demonstrate an absolute increase of at least 5 mm. (Note: appearance of 1 or more new lesions also considered progressions). Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, reference smallest sum diameters while on study. Best response recorded from treatment start until disease progression/recurrence (reference for progressive disease the smallest measurements recorded since treatment started).

  Response evaluation every 6 weeks (in addition to baseline scan, confirmatory scans approximately 6-7 (not less than 4) weeks following initial documentation of objective response). Expected follow up to 5 years, actual study period 9/2010 to 4/2014.

• Percentage of Tumor Shrinkage as a Continuous Variable

  Response is reported as a continuous variable, as % change in tumor size from baseline. Pearson and Spearman correlation coefficients will be used. Reported with 95% two-sided confidence intervals.

  6 weeks

Secondary Outcomes (7)

• Proportion of Tumors Expressing the Expression of Tumor Notch Markers and Stem Cell Markers of Interest in This Population vs Tumor Bank Population

  Up to day 3

• Proportion of Tumors Expressing the Expression of Tumor Notch Markers and Stem Cell Markers of Interest in Participants With Versus Without a Particular Host Genotype Polymorphism

  Up to day 3

• Proportion of Tumors Expressing the Expression of Tumor Notch Markers and Stem Cell Markers of Interest in Participants With vs Without Epidermal Growth Factor Receptor (EGFR) Activating Mutations

  Up to day 3

• Proportion of Tumors Expressing the Expression of Tumor Notch Markers and Stem Cell Markers of Interest in Participants With vs Without Response by RECIST Criteria

  Up to day 3

• Proportion of Tumors Expressing the Expression of Tumor Notch Markers and Stem Cell Markers of Interest in Participants With vs Without Tumor Progression

  Up to 3 months

Study Arms (1)

RO4929097

EXPERIMENTAL

Patients receive oral gamma-secretase inhibitor RO4929097 once daily on days 1-3, 8-10, and 15-17. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Blood and tumor tissue samples are collected for pharmacogenetic, pharmacodynamic, and biomarker studies by IHC, FISH, and TUNEL assay.

Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097; Other: laboratory biomarker analysis; Other: pharmacological study

Interventions

gamma-secretase/Notch signalling pathway inhibitor RO4929097 DRUG

Given orally

Also known as: R4733, RO4929097

RO4929097

laboratory biomarker analysis OTHER

Correlative studies

RO4929097

pharmacological study OTHER

Correlative studies

Also known as: pharmacological studies

RO4929097

Eligibility Criteria

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

You may qualify if:

• Patients must have histologically or cytologically confirmed non-small cell lung cancer that is incurable (stage IV or malignant effusion or recurrent)
• Patients 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 CT scan with cuts at 2.5 or 5 mm
• Patients must have tumor amenable to core biopsy (or by 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
• The patient must have received front line cytotoxic chemotherapy (combination or single agent, with or without the addition of targeted agents) for advanced NSCLC
• Patients will be eligible whether or not they have had a response or stable disease or progression of tumor on the front line cytotoxic therapy, and whether or not they have tumor progression in the interval between their front line therapy and initiation of therapy on this study
• Patients will also be eligible if they have received maintenance cytotoxic chemotherapy (eg pemetrexed) following completion of the front line chemotherapy, provided there had not been tumor progression between the end of the front line chemotherapy and the initiation of the maintenance chemotherapy
• Patients may also have received prior adjuvant chemotherapy or chemoradiotherapy with curative intent (followed by tumor recurrence or progression) before being given the front line therapy for advanced disease
• The last planned front-line therapy cycle or maintenance therapy cycle must have been administered \>= 3 weeks (or \>= 6 weeks after last therapy if it included a nitrosourea or mitomycin-C) and =\< 8 weeks prior to initiation of therapy on this study, although they may be registered on study (prior to drug administration) any time from 0-8 weeks after last planned front-line chemotherapy (to permit correlative studies to be arranged before therapy starts)
• ECOG performance status =\< 2 (Karnofsky \>= 60%)
• Leukocytes \>= 3,000/mcL
• Absolute neutrophil count \>= 1,000/mcL
• Platelets \>= 100,000/mcL
• Total bilirubin within normal institutional limits
• AST(SGOT) and ALT(SGPT) =\< 3 X institutional upper limit of normal
• Creatinine =\< 1.5 X institutional upper limit of normal

You may not qualify if:

• Patients may be registered on the protocol any time from 0-8 weeks after administration of last front-line therapy or maintenance therapy, but should not receive their first treatment on this study until 3-8 weeks after administration of last front-line therapy or maintenance therapy (or 6-8 weeks for prior nitrosoureas or mitomycin-C), and must have recovered adequately from adverse events to meet other eligibility criteria
• Patients may not be receiving any other investigational agents
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to RO4929097 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
• Preclinical studies indicate that RO4929097 is a substrate of CYP3A4 and inducer of CYP3A4 enzyme activity; caution should be exercised when dosing RO4929097 concurrently with CYP3A4 substrates, inducers, and/or inhibitors; furthermore, patients who are taking concurrent medications that are strong inducers/inhibitors or substrates of CYP3A4 should be switched to alternative medications to minimize any potential risk; if such patients cannot be switched to alternative medications, they will be ineligible to participate in this study
• Patients with malabsorption syndrome or other condition that would interfere with intestinal absorption
• Diarrhea \> grade 1 despite appropriate therapy
• Patients who are serologically positive for hepatitis A, B or C are ineligible
• Patients with \> grade 1 (by 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 des 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 because RO4929097 is a Notch pathway inhibiting agent with the potential for teratogenic or abortifacient effects
• HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with RO4929097
• Cardiovascular: baseline QTcF \> 450 msec (male) or QTcF \> 470 msec (female)
• Patients requiring drugs that are known to cause torsades des pointes and/or prolonged QTc intervals are excluded; patients requiring drugs with a possible but unproven association with torsades des pointes and/or QTc prolongation may be eligible, but will require additional electrocardiogram assessments
• Patients who have not recovered to \< CTCAE grade 2 toxicities related to prior therapy are not eligible to participate in this study

Sponsors & Collaborators

• National Cancer Institute (NCI): lead
• M.D. Anderson Cancer Center: collaborator

Study Sites (1)

M D Anderson Cancer Center

Houston, Texas, 77030, United States

Location

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Interventions

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

Limitations and Caveats

The study closed June 2012 with the NCI discontinuation production of the study drug RO4929097.

Results Point of Contact

• Title: George Blumenschein, MD / Professor
• Organization: The University of Texas MD Anderson Cancer Center

CR_Study_Registration@mdanderson.org

713-792-2734

Study Officials

• George Blumenschein

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• 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: September 1, 2010
• Primary Completion: April 1, 2014
• Study Completion: April 1, 2014
• Last Updated: November 18, 2015
• Results First Posted: November 18, 2015

Record last verified: 2013-12

Locations

US (1)