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

This study is ongoing, but not recruiting participants.
Information provided by (Responsible Party):
National Cancer Institute (NCI) Identifier:
First received: September 1, 2010
Last updated: June 9, 2014
Last verified: June 2014

This phase I trial studies the side effects and best dose of RO4929097 and erlotinib hydrochloride when given together in treating patients with stage IV or recurrent non-small cell lung cancer. RO4929097 and erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Condition Intervention Phase
Recurrent Non-small Cell Lung Cancer
Stage IV Non-small Cell Lung Cancer
Drug: erlotinib hydrochloride
Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097
Other: pharmacological study
Other: laboratory biomarker analysis
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Addition of the Gamma-Secretase Inhibitor RO4929097 (IND 109291) to Erlotinib in Patients With Advanced Non-Small Cell Lung Cancer (NSCLC)

Resource links provided by NLM:

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Maximum-tolerated dose of gamma-secretase inhibitor RO4929097 and erlotinib hydrochloride (Dose escalation phase) [ Time Frame: At least 3 weeks after day 1 of course 1 ] [ Designated as safety issue: Yes ]
  • Adverse events (Dose escalation phase) [ Time Frame: Within 30 days of last drug dose ] [ Designated as safety issue: Yes ]
  • Detectable tumor shrinkage or response by RECIST in unselected patients and in patients with intrinsic or acquired erlotinib hydrochloride resistance (Dose escalation phase) [ Time Frame: Up to 12 weeks ] [ Designated as safety issue: No ]
  • Response rate by RECIST 1.1 (Expansion cohort) [ Time Frame: Up to 12 weeks ] [ Designated as safety issue: No ]
  • Change in percentage of tumor shrinkage (Expansion cohort) [ Time Frame: Baseline to 6 weeks ] [ Designated as safety issue: No ]
    We plan to assess differences before and after treatment using a paired-t test on the log-transformed tumor sizes and a Wilcoxon signed-rank test.

Estimated Enrollment: 39
Study Start Date: August 2010
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (erlotinib, RO4929097)
Patients receive erlotinib hydrochloride PO QD on days 1-21 and gamma-secretase inhibitor RO4929097 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
Given PO
Other Names:
  • CP-358,774
  • erlotinib
  • OSI-774
Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097
Given PO
Other Names:
  • R4733
  • RO4929097
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies
Other: laboratory biomarker analysis
Correlative studies

  Show Detailed Description


Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • 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
  • 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
    • Prior therapy is not required
  • Patients with asymptomatic or minimally symptomatic brain metastases will not be required to undergo cranial radiation prior to being considered for this trial, and are eligible provided that it is not anticipated that they will require any of the following over the course of study treatment:

    • Corticosteroids for control of cerebral edema
    • Enzyme-inducing anticonvulsants
    • Radiotherapy, surgery, or other local therapy for the brain metastases
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 60%)
  • Leukocytes >= 3,000/mcL
  • Absolute neutrophil count >= 1,500/mcL
  • Platelets>= 100,000/mcL
  • Hemoglobin >= 9 g/dL
  • Total bilirubin within normal institutional limits
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]) =< 3 X institutional upper limit of normal
  • Creatinine =< 1.5 X institutional upper limit of normal
  • No 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, no patients with hypophosphatemia (serum phosphate below the lower limit of normal for the institution, hypomagnesemia (serum magnesium below the lower limit of normal), or hypokalemia (serum potassium outside normal limits) despite appropriate medical management
  • International normalized ratio (INR) =< 1.7 X upper limit of normal (ULN) and the patient must not have received aspirin or Coumadin and the patient must not have received aspirin or Coumadin within the previous week or a therapeutic dose of a heparin product within the previous 24 hours
  • Fertile patients must use two forms of contraception (i.e., barrier contraception and one other method of contraception) from at least 2 weeks prior to initiation of therapy on this study, for the duration of study participation, and for at least 2 months post-treatment; should a woman become pregnant or suspect she is pregnant while she or her partner are participating in this study and for 2 months after study participation, the patient should inform the treating physician immediately

    • Women of childbearing potential are required to have a negative serum pregnancy test (with a sensitivity of at least 25 mIU/mL) within 14 days prior to the first dose of RO4929097 and a negative serum or urine pregnancy test within 24 hours prior to the first dose of RO4929097; following initiation of therapy with RO4929097, a pregnancy test (serum or urine) will be administered every 3 weeks while on study; a positive urine test must be confirmed by a serum pregnancy test; prior to dispensing RO4929097, the investigator or designate must confirm and document the patient's use of two contraceptive methods, dates of negative pregnancy test, and confirm the patient's understanding of the teratogenic potential of RO4929097
    • Patients with lung cancer may have false-positive pregnancy tests due to production of beta-human chorionic gonadotropin (HCG) by tumor; patients with a positive pregnancy test who are unlikely to be pregnant may be considered for entry on this trial if they are deemed to be unlikely to be pregnant by an obstetrician or gynecologist and if the study sponsor is in agreement with their study entry
    • Female patients of childbearing potential are defined as patients who do not fall into either of the categories listed above and to whom any of the following apply:

      • Patients with regular menses
      • Patients, after menarche with amenorrhea, irregular cycles, or using a contraceptive method that precludes withdrawal bleeding
      • Women who have had tubal ligation
    • Female patients may be considered to NOT be of childbearing potential for the following reasons:

      • The patient has undergone total abdominal hysterectomy with bilateral salpingo-oophorectomy or bilateral oophorectomy
      • The patient is medically confirmed to be menopausal (no menstrual period) for 34 consecutive months
  • Men participating in the study must also use 2 methods of contraception including 1 barrier method from the time of initiation of therapy on the study until 2 months after their last treatment on the study if their sexual partner has childbearing potential; if their sexual partner is already pregnant, 1 barrier method must be used to minimize the probability of exposure of the fetus to potentially toxic concentrations of RO4929097
  • Breastfeeding should be discontinued if the mother is treated with RO4929097
  • Able to swallow oral medications
  • No malabsorption syndrome or other condition that would interfere with intestinal absorption
  • No diarrhea > grade 1 despite appropriate therapy
  • No uncontrolled concurrent illness including, but not limited to, any of the following:

    • Ongoing or active infection requiring systemic therapy (with antibiotics or 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, however patients with any of the following are eligible:

      • Chronic, stable atrial fibrillation
      • Premature atrial or ventricular contractions
      • Sinus tachycardia, provided the rate is controlled at < 115 per minute
      • Sinus bradycardia, provided the rate is > 50 per minute
    • Myocardial infarction within the past 3 months
    • Psychiatric illness or social situations that would limit compliance with study requirements
  • Baseline QTcF =< 450 msec (for male patients) or =< 470 msec (for female patients)
  • No patients requiring drugs that are known to cause torsades de pointes and/or prolonged QTc intervals

    • 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
  • No known serologic positivity for hepatitis A, B, or C
  • No HIV-positive patients requiring combination antiretroviral therapy
  • No history of allergic reactions attributed to compounds of similar chemical or biologic composition to RO4929097, OSI-774, or other agents used in this study
  • Recovered from toxicities (of CTCAE > grade 2) from prior therapy
  • No prior anti-EGFR therapy (small molecule tyrosine kinase inhibitor [TKI] or antibody) (expansion phase only); NOTE: This in contrast to the dose-escalation portion of the study in which patients with prior anti-EGFR therapy will be eligible
  • At least 4 weeks since prior anticancer systemic therapy or radiotherapy (2 weeks for radiotherapy that was restricted to distal limbs such as femur below the trochanter, humerus, or more distal limb areas)

    • 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
  • No other concurrent investigational agents
  • No concurrent medications (other than erlotinib hydrochloride) that are strong inducers/inhibitors or substrates of CYP3A4
  • No concurrent medications with narrow therapeutic indices that are metabolized by cytochrome P450 (CYP450), including warfarin sodium (Coumadin)
  • No concurrent medications or food that may interfere with the metabolism of gamma-secretase inhibitor RO4929097 (RO4929097) or erlotinib hydrochloride, including ketoconazole, grapefruit, and grapefruit juice
  • No other concurrent anticancer agent or therapy
  • No pregnant women
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT01193881

United States, Texas
M D Anderson Cancer Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
Principal Investigator: Don Gibbons M.D. Anderson Cancer Center
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI) Identifier: NCT01193881     History of Changes
Other Study ID Numbers: NCI-2010-01975, NCI-2010-01975, 2009-0769, 8508, P30CA016672
Study First Received: September 1, 2010
Last Updated: June 9, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Carcinoma, Non-Small-Cell Lung
Lung Neoplasms
Carcinoma, Bronchogenic
Bronchial Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions processed this record on September 16, 2014