RO4929097 and Whole-Brain Radiation Therapy or Stereotactic Radiosurgery in Treating Patients With Brain Metastases From Breast Cancer

NCT01217411 | Terminated Phase 1 Results

• 10 other identifiers: NCI-2011-02533CDR0000686136MDA-2009-05822009-05828543N01CM00039P30CA016672U01CA062461U01CA069852U01CA076576
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 2

Brief Summary

This randomized phase I/II trial studies the side effects and the best dose of RO4929097 (gamma-secretase/Notch signalling pathway inhibitor RO4929097) when given together with whole-brain radiation therapy or stereotactic radiosurgery and to see how well it works compared to whole-brain radiation therapy or stereotactic radiosurgery alone in treating patients with breast cancer or other cancers (such as lung cancer or melanoma) that have spread to the brain. RO4929097 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Whole-brain radiation therapy uses high energy x-rays deliver radiation to the entire brain to treat tumors that can and cannot be seen. Stereotactic radiosurgery may be able to deliver x-rays directly to the tumor and cause less damage to normal tissue. It is not yet known whether giving RO4929097 together with whole-brain radiation therapy or stereotactic radiosurgery may kill more tumor cells.

Conditions

Adult Solid Neoplasm; Extensive Stage Lung Small Cell Carcinoma; HER2/Neu Negative; HER2/Neu Positive; Male Breast Carcinoma; Metastatic Malignant Neoplasm in the Brain; Recurrent Breast Carcinoma; Recurrent Lung Non-Small Cell Carcinoma; Recurrent Lung Small Cell Carcinoma; Recurrent Melanoma; Stage IV Breast Cancer AJCC v6 and v7; Stage IV Cutaneous Melanoma AJCC v6 and v7; Stage IV Lung Non-Small Cell Cancer AJCC v7

Outcome Measures

Primary Outcomes (3)

• Phase 1 Arm I Maximum-tolerated Dose (MTD) of RO4929097 in Combination With Whole-brain Radiotherapy (WBRT)

  Maximum-tolerated dose (MTD) of RO4929097 in combination with WBRT, determined according to incidence of dose limiting toxicity (DLT) graded using the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (Phase I)

  4 weeks

• Phase 1 Arm II MTD of RO4929097 in Combination With Stereotactic Surgery (SRS)

  MTD of RO4929097 in combination with SRS, determined according to incidence of DLT graded using the NCI CTCAE version 4.0 (phase I)

  4 weeks

• Response Rate (Complete or Partial Response)

  Only participants with measurable disease present at baseline, received at least 6 weeks of therapy, and had disease re-evaluated considered evaluable for response. Complete Response (CR): Disappearance all lesions; Partial Response (PR): =/\>50% decrease in sum bidimensional products all lesions reference baseline sum of bidimensional products of all lesions; Progressive Disease (PD): \>25% increase in sum bidimensional products of lesions, or progression of any treated lesion not target lesion, or appearance of 1 or \> new lesions at least 6 mm in unidimensional size. Stable Disease (SD): Neither sufficient shrinkage for PR nor increase for PD, reference smallest sum of bidimensional products of all lesions.

  12 weeks

Study Arms (2)

Arm I (WBRT or SRS)

ACTIVE COMPARATOR

Patients with \>= 4 brain lesions undergo WBRT as in phase I and patients with =\< 3 brain lesions undergo SRS as in phase I.

Procedure: Cognitive Assessment; Other: Laboratory Biomarker Analysis; Radiation: Stereotactic Radiosurgery; Radiation: Whole-Brain Radiotherapy

Arm II (WBRT or SRS and RO4929097)

EXPERIMENTAL

Patients with \>= 4 brain lesions receive RO4929097 and undergo WBRT as in phase I and patients with =\< 3 brain lesions receive RO4929097 and undergo SRS as in phase I.

Procedure: Cognitive Assessment; Drug: Gamma-Secretase Inhibitor RO4929097; Other: Laboratory Biomarker Analysis; Radiation: Stereotactic Radiosurgery; Radiation: Whole-Brain Radiotherapy

Interventions

Cognitive Assessment PROCEDURE

Ancillary studies

Arm I (WBRT or SRS); Arm II (WBRT or SRS and RO4929097)

Gamma-Secretase Inhibitor RO4929097 DRUG

Given PO

Also known as: R04929097, RG-4733, RO4929097

Arm II (WBRT or SRS and RO4929097)

Laboratory Biomarker Analysis OTHER

Correlative studies

Arm I (WBRT or SRS); Arm II (WBRT or SRS and RO4929097)

Stereotactic Radiosurgery RADIATION

Undergo SRS

Also known as: SRS, Stereotactic External Beam Irradiation, stereotactic external-beam radiation therapy, Stereotactic Radiation Therapy, Stereotactic Radiotherapy, stereotaxic radiation therapy, stereotaxic radiosurgery

Arm I (WBRT or SRS); Arm II (WBRT or SRS and RO4929097)

Whole-Brain Radiotherapy RADIATION

Undergo WBRT

Also known as: WBRT, whole-brain radiation therapy

Arm I (WBRT or SRS); Arm II (WBRT or SRS and RO4929097)

Eligibility Criteria

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

You may qualify if:

• Patients who have histologically or cytologically confirmed breast cancer or other cancers (such as lung cancer, melanoma, etc) with newly diagnosed metastatic disease to the brain will be eligible for the Phase 1 study only, however, those patients who have available systemic therapeutic options with a demonstrated survival benefit will not be eligible; for Phase 2, patients must have histologically or cytologically confirmed estrogen receptor negative breast cancer with newly diagnosed metastatic disease to the brain
• Patients must have measurable disease in the brain, defined as at least one lesion that can be accurately measured in at least two dimensions (longest diameter and its longest perpendicular diameter to be recorded)
• There is no limit on type or number of prior therapies, except that prior therapy with notch inhibitors is not allowed, and patients should not have received prior cranial radiation; therapy naïve patients are eligible; at least 14 days (2 weeks) must have elapsed from any prior experimental therapy, chemotherapy or radiotherapy; toxicities from prior chemotherapy or radiotherapy should have resolved to \< grade 2; patients with newly diagnosed brain metastases who have received therapeutic regimens with well-characterized, delayed toxicity (e.g. hematologic toxicity observed following carmustine \[BCNU\] or mitomycin C) will not receive experimental therapy until the patient has adequately recovered from all drug related toxicities
• Karnofsky performance status (KPS) \>= 70%; Recursive Partitioning Analysis (RPA) class I or II; a small feasibility cohort of 10 RPA class III (KPS \< 70%) patients may be enrolled, however these patients, if enrolled will not be included in the efficacy analysis
• Hemoglobin \>= 9g/dL
• Absolute neutrophil count \>= 1,000/mcL
• Platelets \>= 100,000/mcL
• Total bilirubin within normal institutional limits
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) =\< 2.5 x institutional upper limit of normal
• Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 2.5 x institutional upper limits of normal
• Creatinine within normal institutional limits OR creatinine clearance \>= 60 mL/min/1.73 m\^2 for patients with creatinine levels above institutional normal
• Tumor HER2/neu status may be positive or negative
• Women of childbearing potential and men must use two forms of contraception (i.e., barrier contraception and one other method of contraception) for the duration of study participation, and for at least 12 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 12 months after study participation, the patient should inform the treating physician immediately; prior to dispensing RO4929097, the investigator must confirm and document the patient's agreement to the use of two contraceptive methods, dates of negative pregnancy test, and confirm the patient's understanding of the teratogenic potential of RO4929097
• Ability to understand and the willingness to sign a written informed consent document
• A tumor site (outside the central nervous system) for needle biopsy for research purposes is preferable

You may not qualify if:

• At least 14 days (2 weeks) must have elapsed from any prior experimental therapy, chemotherapy or radiotherapy; toxicities from prior chemotherapy or radiotherapy should have resolved to \< grade 2
• Patients may not be receiving any other investigational agents
• Patients with leptomeningeal metastases should be excluded from this clinical trial
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to RO4929097
• Patients taking medications with narrow therapeutic indices that are metabolized by cytochrome P450 (CYP450), including warfarin sodium (Coumadin®) are ineligible
• Patients taking medications that are generally accepted by the QTdrugs.org Advisory Board to carry a risk of torsades de pointes, including antiemetics, are ineligible
• Preclinical studies indicate that RO4929097 is a substrate of CYP450 family 3, subfamily A, polypeptide 4 (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; patients must be able to swallow tablets
• Patients who are known to be serologically positive for hepatitis A, B or C, or have a history of liver disease, other forms of hepatitis or cirrhosis are ineligible
• Patients with uncontrolled hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia or hypokalemia defined as less than the lower limit of normal for the institution, despite adequate electrolyte supplementation are excluded from this study
• Uncontrolled electrolyte abnormalities including hypocalcemia, hypomagnesemia, and hypokalemia; uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure (New York Heart Association \[NYHA\] class III or IV), unstable angina pectoris, a history of torsades de pointes or other significant cardiac arrhythmias, stable atrial fibrillation, or psychiatric illness/social situations that would limit compliance with study requirements
• Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with RO4929097
• Cardiovascular: baseline QTcF \> 450 msec (male) or QTcF \> 470 msec (female)
• Patients who have not recovered to \< Common Terminology Criteria for Adverse Events (CTCAE) grade 2 toxicities related to prior therapy are not eligible to participate in this study
• A requirement for antiarrhythmics or other medications known to prolong QTc

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (2)

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

M D Anderson Cancer Center

Houston, Texas, 77030, United States

Location

MeSH Terms

Conditions

Breast Neoplasms, Male; Brain Neoplasms; Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Small Cell Lung Carcinoma; Melanoma

Interventions

Mental Status and Dementia Tests; 2,2-dimethyl-N-(6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-N'-(2,2,3,3,3-pentafluoropropyl)malonamide; Radiosurgery

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Central Nervous System Neoplasms; Nervous System Neoplasms; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Diseases; Respiratory Tract Diseases; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms

Intervention Hierarchy (Ancestors)

Neuropsychological Tests; Psychological Tests; Behavioral Disciplines and Activities; Radiotherapy; Therapeutics; Stereotaxic Techniques; Neurosurgical Procedures; Surgical Procedures, Operative; Investigative Techniques

Limitations and Caveats

Due to small number of patients enrolled on study, researchers were unable to make meaningful conclusions from the data.

Results Point of Contact

• Title: Morris D. Groves, MD / Professor
• Organization: University of Texas (UT) MD Anderson Cancer Center

mgroves@mdanderson.org

713-792-2573

Study Officials

• Morris D Groves

  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 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 7, 2010
• First Posted: October 8, 2010
• Study Start: October 1, 2010
• Primary Completion: November 30, 2011
• Study Completion: November 30, 2011
• Last Updated: November 19, 2024
• Results First Posted: February 6, 2015

Record last verified: 2024-10

Locations

US (2)