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A Phase 1 Study of RO4929097 (NSC749225) in Combination With Capecitabine in Refractory Solid Tumors


Phase 1
18 Years
N/A
Open (Enrolling)
Both
Adult Grade III Lymphomatoid Granulomatosis, Adult Nasal Type Extranodal NK/T-cell Lymphoma, AIDS-related Diffuse Large Cell Lymphoma, AIDS-related Diffuse Mixed Cell Lymphoma, AIDS-related Diffuse Small Cleaved Cell Lymphoma, AIDS-related Immunoblastic Large Cell Lymphoma, AIDS-related Lymphoblastic Lymphoma, AIDS-related Peripheral/Systemic Lymphoma, AIDS-related Primary CNS Lymphoma, AIDS-related Small Noncleaved Cell Lymphoma, Anaplastic Large Cell Lymphoma, Angioimmunoblastic T-cell Lymphoma, Cutaneous B-cell Non-Hodgkin Lymphoma, Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue, HER2-negative Breast Cancer, HIV-associated Hodgkin Lymphoma, Intraocular Lymphoma, Male Breast Cancer, Nodal Marginal Zone B-cell Lymphoma, Post-transplant Lymphoproliferative Disorder, Primary Central Nervous System Hodgkin Lymphoma, Primary Central Nervous System Non-Hodgkin Lymphoma, Recurrent Adult Burkitt Lymphoma, Recurrent Adult Diffuse Large Cell Lymphoma, Recurrent Adult Diffuse Mixed Cell Lymphoma, Recurrent Adult Diffuse Small Cleaved Cell Lymphoma, Recurrent Adult Grade III Lymphomatoid Granulomatosis, Recurrent Adult Hodgkin Lymphoma, Recurrent Adult Immunoblastic Large Cell Lymphoma, Recurrent Adult Lymphoblastic Lymphoma, Recurrent Adult T-cell Leukemia/Lymphoma, Recurrent Breast Cancer, Recurrent Colon Cancer, Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma, Recurrent Grade 1 Follicular Lymphoma, Recurrent Grade 2 Follicular Lymphoma, Recurrent Grade 3 Follicular Lymphoma, Recurrent Mantle Cell Lymphoma, Recurrent Marginal Zone Lymphoma, Recurrent Mycosis Fungoides/Sezary Syndrome, Recurrent Rectal Cancer, Recurrent Small Lymphocytic Lymphoma, Small Intestine Lymphoma, Splenic Marginal Zone Lymphoma, Stage III Adult Burkitt Lymphoma, Stage III Adult Diffuse Large Cell Lymphoma, Stage III Adult Diffuse Mixed Cell Lymphoma, Stage III Adult Diffuse Small Cleaved Cell Lymphoma, Stage III Adult Hodgkin Lymphoma, Stage III Adult Immunoblastic Large Cell Lymphoma, Stage III Adult Lymphoblastic Lymphoma, Stage III Adult T-cell Leukemia/Lymphoma, Stage III Colon Cancer, Stage III Cutaneous T-cell Non-Hodgkin Lymphoma, Stage III Grade 1 Follicular Lymphoma, Stage III Grade 2 Follicular Lymphoma, Stage III Grade 3 Follicular Lymphoma, Stage III Mantle Cell Lymphoma, Stage III Marginal Zone Lymphoma, Stage III Mycosis Fungoides/Sezary Syndrome, Stage III Rectal Cancer, Stage III Small Lymphocytic Lymphoma, Stage IIIA Breast Cancer, Stage IIIB Breast Cancer, Stage IIIC Breast Cancer, Stage IV Adult Burkitt Lymphoma, Stage IV Adult Diffuse Large Cell Lymphoma, Stage IV Adult Diffuse Mixed Cell Lymphoma, Stage IV Adult Diffuse Small Cleaved Cell Lymphoma, Stage IV Adult Hodgkin Lymphoma, Stage IV Adult Immunoblastic Large Cell Lymphoma, Stage IV Adult Lymphoblastic Lymphoma, Stage IV Adult T-cell Leukemia/Lymphoma, Stage IV Breast Cancer, Stage IV Colon Cancer, Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma, Stage IV Grade 1 Follicular Lymphoma, Stage IV Grade 2 Follicular Lymphoma, Stage IV Grade 3 Follicular Lymphoma, Stage IV Mantle Cell Lymphoma, Stage IV Marginal Zone Lymphoma, Stage IV Mycosis Fungoides/Sezary Syndrome, Stage IV Rectal Cancer, Stage IV Small Lymphocytic Lymphoma, Unspecified Adult Solid Tumor, Protocol Specific, Waldenström Macroglobulinemia

Thank you

Trial Information

A Phase 1 Study of RO4929097 (NSC749225) in Combination With Capecitabine in Refractory Solid Tumors


PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of RO4929097 and capecitabine administered
in subjects with advanced solid tumors. (Part 1) II. To describe the dose-limiting
toxicities (DLTs) of combined RO492097 and capecitabine. (Part 1) III. To determine the
safety of RO4929097 and capecitabine administered in combination. (Part 1) IV. To determine
the safety of RO4929097 and capecitabine in subjects with metastatic CRC. (Part 2a) V. To
evaluate the safety of RO4929097 and capecitabine in combination for subjects with HER2/neu
negative MBC. (Part 2b)

SECONDARY OBJECTIVES:

I. To determine the clinical activity of RO4929097 and capecitabine administered in
combination to subjects with advanced solid tumors. (Parts 1, 2a, and 2b) II. To evaluate
the changes in the expression of Notch1 signaling pathway members and downstream targets of
Notch by PCR including HEs1, 3 and 5; Hey 1 and 2 after treatment with RO4929097 at the MTD
expansion cohorts. (Parts 1, 2a, and 2b) III. To determine the pharmacokinetic and
pharmacogenomic profiles of the combination of RO4929097 and capecitabine. (Parts 1, 2a, and
2b) IV. To determine the progression-free survival (PFS) of RO4929097 and capecitabine when
administered at the MTD level in patients with metastatic colorectal cancer (CRC) and a
history of 1 or 2 prior therapies. (Part 2a) V. To determine the response and overall
survival (OS) rates following RO4929097 and capecitabine administration at the MTD level in
subjects with metastatic CRC. (Part 2a) VI. To determine the overall response rate (ORR) of
RO4929097 and capecitabine when administered at the MTD level to subjects when administered
first or second line for HER2/neu negative metastatic breast cancer (MBC). (Part 2b) V. To
determine the progression-free and overall survival rates following RO4929097 and
capecitabine administration at the MTD level in subjects with HER2/neu negative MBC. (Part
2b)

OUTLINE: This is a multicenter, dose-escalation study of gamma-secretase inhibitor
RO4929097.

Patients receive oral gamma-secretase inhibitor RO4929097 once daily on days 1-3, 8-10, and
15-17 and oral capecitabine twice daily on days 1-14. Courses repeat every 21 days in the
absence of disease progression or unacceptable toxicity.

Patients may undergo tumor biopsy before and after treatment for biomarker analysis and
blood sample collection periodically for pharmacokinetic and pharmacogenomic studies.

After completion of study treatment, patients are followed up for 30 days (Part 1) or every
3 months (Parts 2a and 2b).


Inclusion Criteria:



- Patients must have histologically or cytologically confirmed advanced or metastatic
solid tumor; patients with lymphoma will be eligible

- 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 >=
20 mm with conventional techniques or as >= 10 mm with spiral CT scan

- Patients must be at least 4 weeks since prior chemotherapy, 6 weeks if the last
regimen included BCNU or mitomycin C; prior radiation is allowed as long as the
radiation was completed 4 weeks prior to study treatment and no more than 35% of
marrow irradiated

- Life expectancy of greater than 3 months

- ECOG performance status =< 2 (Karnofsky >= 60%)

- Hemoglobin >= 9 g/dL

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Total bilirubin within normal institutional limits

- AST (SGOT)/ALT (SGPT) =< 2.5 X institutional upper limit 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; a 24
hour urine collection and creatinine clearance can be measured if indicated

- Treated, stable brain metastases are allowed; patients must be four weeks from
radiation with stable brain imaging and off any medications used to treat brain
metastases, excepting those anti-epileptics not metabolized by cytochrome P450

- Women of childbearing potential and men must use two forms of contraception (i.e.,
barrier contraception and one other method of contraception) at least 4 weeks prior
to study entry, 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

- Women of childbearing potential are required to have a negative serum pregnancy test
(with a sensitivity of at least 25 mIU/mL) within 10-14 days and within 24 hours
prior to the first dose of RO4929097 (serum or urine); a pregnancy test (serum or
urine) will be administered every 4 weeks if their menstrual cycles are regular or
every 2 weeks if their cycles are irregular while on study within the 24-hour period
prior to the administration of RO4929097; a positive urine test must be confirmed by
a serum pregnancy test; prior to dispensing RO4929097, the investigator 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

- Female patients of childbearing potential are defined as follows:

- 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 NOT to 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 24
consecutive months

- Pre-pubertal females. The parent or guardian of young female patients who have
not yet started menstruation should verify that menstruation has not begun. If
a young female patient reaches menarche during the study, then she is to be
considered as a woman of childbearing potential from that time forward

- Patients must demonstrate an ability to understand and the willingness to sign a
written informed consent document

- 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

- PART 2A (MTD EXPANSION COLORECTAL CANCER):

- For this cohort patients must have histologically or cytologically documented
advanced or metastatic colorectal cancer; patients must have had at least one prior
chemotherapy regimen for their disease but no more than 2

- All 5 patients in this cohort must be willing and able to have tumor biopsies
performed as part of the correlative studies associated with this trial

- PART 2B (MTD EXPANSION BREAST CANCER):

- For this cohort, patients must have histologically or cytologically documented
advanced or metastatic breast cancer

- Patient must be HER2/neu negative; HER2 negative will be defined as HER2 neither
over-expressed or amplified; HER2 will be considered NOT over-expressed if the tumor
stains as 0 or 1+ for HER2 by immunohistochemistry (IHC); if the IHC for HER2 is 2+,
fluorescence in-site hybridization (FISH) ratio must be less than 2 to be considered
NOT amplified; any tumor for which only FISH was performed must have a ratio of less
than 2 to be considered NOT amplified

- All 5 patients in this breast cancer cohort must be willing and able to have tumor
biopsies performed as part of the correlative studies associated with this trial

Exclusion 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 capecitabine

- Patients taking medications with narrow therapeutic indices that are metabolized by
cytochrome P450 (CYP450), including warfarin sodium (Coumadin®) are ineligible

- Patients with malabsorption syndrome or other condition that would interfere with
intestinal absorption; patients must be able to swallow tablets

- Patients who are 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; note: it is acceptable to use corrected calcium when interpreting calcium
levels

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, and a
history of torsades de pointes or other significant cardiac arrhythmia other than
chronic, 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

- HIV-positive patients, who are not on anti-retroviral therapy but have CD4 cells less
than 200, should be excluded; HIV-positive patients are eligible if they are on HAART
(highly active anti-retroviral therapy) which are not CYP3A4 substrates, inducers
and/or inhibitors and meet all other criteria

- Cardiovascular: baseline QTcF > 450 msec

- Patients with known dihydropyrimidine dehydrogenase (DPD) deficiency enzyme are
excluded

- Patients who have not recovered to < 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

- PART2B (MTD EXPANSION BREAST CANCER):

- Patients may not have had more than 1 prior cytotoxic chemotherapy for metastatic
disease; prior endocrine or immunotherapy regimens for metastatic disease will not be
counted as cytotoxic

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

MTD of RO4929097 and capecitabine, defined as that dose level at which less than one-third of patients experience a dose-limiting toxicity (DLT) graded according to NCI CTCAE version 4.0 (Part 1)

Outcome Time Frame:

Up to 21 days

Safety Issue:

Yes

Principal Investigator

Noelle LoConte

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Wisconsin Hospital and Clinics

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2012-02918

NCT ID:

NCT01158274

Start Date:

June 2010

Completion Date:

Related Keywords:

  • Adult Grade III Lymphomatoid Granulomatosis
  • Adult Nasal Type Extranodal NK/T-cell Lymphoma
  • AIDS-related Diffuse Large Cell Lymphoma
  • AIDS-related Diffuse Mixed Cell Lymphoma
  • AIDS-related Diffuse Small Cleaved Cell Lymphoma
  • AIDS-related Immunoblastic Large Cell Lymphoma
  • AIDS-related Lymphoblastic Lymphoma
  • AIDS-related Peripheral/Systemic Lymphoma
  • AIDS-related Primary CNS Lymphoma
  • AIDS-related Small Noncleaved Cell Lymphoma
  • Anaplastic Large Cell Lymphoma
  • Angioimmunoblastic T-cell Lymphoma
  • Cutaneous B-cell Non-Hodgkin Lymphoma
  • Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue
  • HER2-negative Breast Cancer
  • HIV-associated Hodgkin Lymphoma
  • Intraocular Lymphoma
  • Male Breast Cancer
  • Nodal Marginal Zone B-cell Lymphoma
  • Post-transplant Lymphoproliferative Disorder
  • Primary Central Nervous System Hodgkin Lymphoma
  • Primary Central Nervous System Non-Hodgkin Lymphoma
  • Recurrent Adult Burkitt Lymphoma
  • Recurrent Adult Diffuse Large Cell Lymphoma
  • Recurrent Adult Diffuse Mixed Cell Lymphoma
  • Recurrent Adult Diffuse Small Cleaved Cell Lymphoma
  • Recurrent Adult Grade III Lymphomatoid Granulomatosis
  • Recurrent Adult Hodgkin Lymphoma
  • Recurrent Adult Immunoblastic Large Cell Lymphoma
  • Recurrent Adult Lymphoblastic Lymphoma
  • Recurrent Adult T-cell Leukemia/Lymphoma
  • Recurrent Breast Cancer
  • Recurrent Colon Cancer
  • Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma
  • Recurrent Grade 1 Follicular Lymphoma
  • Recurrent Grade 2 Follicular Lymphoma
  • Recurrent Grade 3 Follicular Lymphoma
  • Recurrent Mantle Cell Lymphoma
  • Recurrent Marginal Zone Lymphoma
  • Recurrent Mycosis Fungoides/Sezary Syndrome
  • Recurrent Rectal Cancer
  • Recurrent Small Lymphocytic Lymphoma
  • Small Intestine Lymphoma
  • Splenic Marginal Zone Lymphoma
  • Stage III Adult Burkitt Lymphoma
  • Stage III Adult Diffuse Large Cell Lymphoma
  • Stage III Adult Diffuse Mixed Cell Lymphoma
  • Stage III Adult Diffuse Small Cleaved Cell Lymphoma
  • Stage III Adult Hodgkin Lymphoma
  • Stage III Adult Immunoblastic Large Cell Lymphoma
  • Stage III Adult Lymphoblastic Lymphoma
  • Stage III Adult T-cell Leukemia/Lymphoma
  • Stage III Colon Cancer
  • Stage III Cutaneous T-cell Non-Hodgkin Lymphoma
  • Stage III Grade 1 Follicular Lymphoma
  • Stage III Grade 2 Follicular Lymphoma
  • Stage III Grade 3 Follicular Lymphoma
  • Stage III Mantle Cell Lymphoma
  • Stage III Marginal Zone Lymphoma
  • Stage III Mycosis Fungoides/Sezary Syndrome
  • Stage III Rectal Cancer
  • Stage III Small Lymphocytic Lymphoma
  • Stage IIIA Breast Cancer
  • Stage IIIB Breast Cancer
  • Stage IIIC Breast Cancer
  • Stage IV Adult Burkitt Lymphoma
  • Stage IV Adult Diffuse Large Cell Lymphoma
  • Stage IV Adult Diffuse Mixed Cell Lymphoma
  • Stage IV Adult Diffuse Small Cleaved Cell Lymphoma
  • Stage IV Adult Hodgkin Lymphoma
  • Stage IV Adult Immunoblastic Large Cell Lymphoma
  • Stage IV Adult Lymphoblastic Lymphoma
  • Stage IV Adult T-cell Leukemia/Lymphoma
  • Stage IV Breast Cancer
  • Stage IV Colon Cancer
  • Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma
  • Stage IV Grade 1 Follicular Lymphoma
  • Stage IV Grade 2 Follicular Lymphoma
  • Stage IV Grade 3 Follicular Lymphoma
  • Stage IV Mantle Cell Lymphoma
  • Stage IV Marginal Zone Lymphoma
  • Stage IV Mycosis Fungoides/Sezary Syndrome
  • Stage IV Rectal Cancer
  • Stage IV Small Lymphocytic Lymphoma
  • Unspecified Adult Solid Tumor, Protocol Specific
  • Waldenström Macroglobulinemia
  • Acquired Immunodeficiency Syndrome
  • HIV Infections
  • Breast Neoplasms
  • Burkitt Lymphoma
  • Colonic Neoplasms
  • Rectal Neoplasms
  • Hodgkin Disease
  • Immunoblastic Lymphadenopathy
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, T-Cell
  • Leukemia-Lymphoma, Adult T-Cell
  • Lymphoma
  • Lymphoma, Follicular
  • Lymphoma, Large B-Cell, Diffuse
  • Lymphoma, Non-Hodgkin
  • Lymphomatoid Granulomatosis
  • Lymphoproliferative Disorders
  • Waldenstrom Macroglobulinemia
  • Mycoses
  • Mycosis Fungoides
  • Sezary Syndrome
  • Lymphoma, B-Cell
  • Lymphoma, Large-Cell, Immunoblastic
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Lymphoma, T-Cell
  • Lymphoma, T-Cell, Cutaneous
  • Lymphoma, Large-Cell, Anaplastic
  • Breast Neoplasms, Male
  • Lymphoma, B-Cell, Marginal Zone
  • Lymphoma, Extranodal NK-T-Cell
  • Neoplasms
  • Lymphoma, Mantle-Cell

Name

Location

University of Wisconsin Hospital and ClinicsMadison, Wisconsin  53792-0001