MDACC Study Summary 2007-0221

Study Summary
No. 2007-0221:.......Advanced Cancers; Breast......Faye M. Johnson......Thoracic and Head and Neck Med

Study Summary Title



Study Summary Number:	2007-0221

Study Title:	A Phase I/Ib, multi-center, open-label study of BEZ235, administered orally on a continuous daily dosing schedule in adult patients with advanced solid malignancies including patients with advanced breast cancer

Physician

New Patient Referral



Name:	Faye M. Johnson	Patients Call:	800-392-1611 (in U.S.A.) 713-792-6161 (outside U.S.A.)

Dept:	Thoracic and Head and Neck Med	Referring MD Call:	800-392-1611 (in U.S.A.) 713-792-6161 (outside U.S.A.)

Phone:	713-792-6363 Contact us about clinical trials

General Information



Disease Group:	Advanced Cancers Breast	Supported By:	Novartis

Phase of Study:	Phase I/Phase II	Return Visit:	Each cycle = 28 days. Cycle 1= 5 visits. Cycle 2 = 4 visits. Cycle 3 and up = 3 visits. Plus End of Treatment visit.

Treatment Agents:	BEZ235	Home Care:	N/A

Treatment Loc:	Both at MDACC & outside MDACC at one or more Collaborating Sites or Institutions

Estimated Length of Stay in Houston:	For pts enrolled in dose-escalation or in safety dose expansion cohort, Days 1,8 and 28 require blood sample collection (3 ml) at 10 time points. Pt may stay in hospital or nearby hotel room on those 3 days.


Description/ Intervention:	The goal of this clinical research study is to find the highest tolerable dose of BEZ235 that can be given in patients with advanced cancer. The safety and effectiveness of study drug will also be studied.

Study Objectives / Outcomes

Primary objectives

Dose escalation part
· To determine the Maximum Tolerated Dose (MTD) based on the incidence rate of Dose Limiting Toxicities (DLT) of BEZ235, administered orally to adult patients with advanced solid tumors, which have progressed despite standard therapy or for whom no standard anticancer therapy exists.

The MTD will be determined for at least one of the following treatment regimens:

Dose expansion part
· To assess the safety and tolerability of BEZ235 administered to patients at the MTD level (Safety expansion arm). The safety expansion will be performed with the formulation selected based on PK properties as determined during the dose escalation part and convenience of administration.

To achieve this objective, the type, frequency and severity of adverse drug reactions will be assessed in the patients based on the CTCAE Version 3.0 (unless otherwise specified).

Secondary objectives

To assess the safety and tolerability of BEZ235 HCG and BEZ235 SDS.
To characterize the single and multiple-dose pharmacokinetics (PK) profiles of oral BEZ235 on a continuous daily dosing schedule, administered as single-agent treatment and in combination with trastuzumab.
To assess changes in target and downstream PD markers (e.g. p-AKT, p-S6) pre-and post-treatment in tumor tissue biopsies (where available and accessible) or archival material (pre-treatment only), and blood (glucose metabolism markers-fasting insulin, C-peptide and glucose,) as a measure of PI3K inhibition.
To assess the mutational status of the PIK3CA, PTEN and p53 genes in pre-treatment tumor biopsies (where available and accessible) and/or archival tumor material.
To assess the protein level of PTEN and p-Akt (IHC) in pre-treatment tumor biopsies (where available and accessible) and/or archival tumor material.
To determine, where appropriate, the HER2, EGFR, erbB3, ER, and PgR status in pre-treatment tumor biopsies (where available and accessible) and/or archival tumor material, pending tissue and assay (erbB3) availability, This analysis will be performed based upon responses to the drug treatment.
To investigate treatment induced cellular responses such as apoptosis and/or inhibition of proliferation in tumor biopsies (where available and accessible) and peripheral blood .
To assess changes in cellular physiology as an early indicator of efficacy by PET imaging, pre- and post-therapy in all patients.
To evaluate the anti-tumor activity (tumor response) of BEZ235, as single-agent treatment and in combination with trastuzumab in patients with solid tumors and separately, if possible, in patients with Cowden Syndrome, (including the patients who have retrospectively been diagnosed to have CS). Assessment of the anti-tumor activity in CS patients will also include cutaneous hamartomas.

Exploratory objectives

Study Status Information



Study Activation / Registration Date:	12/21/2007

IRB Review and Approval Date:	07/24/2007

Study Type:	Phase Ii Or Phase I/Ii

Recruitment Status:	Closed

Projected Accrual:	120

Enrollment Eligibility

If you do not meet the enrollment eligibility, there may be other treatment options for you. Please Contact the Referral Office for more information.

Inclusion Criteria:

1) [Single agent dose escalation arm]: Patients with histologically-confirmed, advanced unresectable solid tumors including CS patients who have progressed on (or not been able to tolerate) standard therapy within three months before screening visit or for whom no standard anticancer therapy exists.Continued in Inclusion # 2

2) In the case of patients with NSCLC, HRPC, and Ovarian Cancer, the following criteria apply: a) metastatic NSCLC: PD during single-agent treatment with RTK inhibitor. To be eligible, the minimum RTKi treatment duration must be three months and the tumor must have responded during treatment (SD or OR) Continued in inclusion #3

3) b) metastatic hormone-refractory prostate cancer: PD is defined as documented increase of PSA (Prostate Cancer Working Group 2 (PCWG2) criteria) or as documented radiologic PD. c) metastatic Ovarian Cancer: PD is defined as documented radiologic PD with or without documented increase of CA-125 levels.

4) [Combination Dose Escalation arm] Female patients with histologically confirmed, metatstatic HER2+ Breast Cancer, after failure of trastuzumab treatment. Eligible patients will have to have tumors carrying molecular alterations of PIK3CA and/or PTEN. Failure of trastuzumab treatment is defined as disease progression during trastuzumab maintenance treatment given as part of an adjuvant treatment regimen or as part of a treatment regimen for metastatic disease. Continued in Inclusion #5.

5) The following rules should be used for the assessment of the HER2 expression status: IHC+++: IHC results, if obtained with satndard IHC methods, is acceptable; IHC++ or IHC+: Confirmation by FISH is needed. Tumors tested by FISH must be positive by specific FISH assay for the amplification of HER2.

6) [Single agent safety expansion arm]: Patients with histologically-confirmed , advanced unresectable solid tumors including CS patients who have progressed on (or not been able to tolerate) standard therapy within three months before screening visit (as per amendment 4) or for whom no standard anticancer therapy exist. Patients will be pre-screened for molecular alterations affecting PIK3CA and/or PTEN. Patients with NSCLC will be pre-screened for EGFR mutation.

7) [Dose escalation and safety expansion arm]: at least one measurable or non-measurable lesion as defined by RECIST criteria for solid tumors. All patients must have at least one measurable lesion as defined by RECIST criteria for solid tumors. Prostate cancer and ovarian cancer patients may be enrolled on the basis of elevated PSA and CA-125 levels, respectively, in the absence of any measurable lesion. [Dose escalation part and safety expansion arm]: Patients with Cowden Syndrome with a genetically confirmed and documented mutation of the susceptibility gene 10q22-23.

8) Patients who fulfill the following criteria will be eligible for PET assessments: • Indications: tumor types known to have a high FDG uptake, such as breast, lung, GIST, melanoma, colorectal, lymphoma • At least one lesion must be measurable ( >2cm) • To be eligible for follow-up scans, patients should have uptake of the tracer in at least one lesion where the tumor-muscle ratio is >2. • Able to lie still and flat on the PET table.

9) Availability of a representative tumor tissue specimen. Archival tumor tissue is allowed. As per amendmend 4, fresh biopsies must be collected whenever feasible and accessible according to the investigator's judgment, until paired biopsies from 10 patients in the single agent safety expansion arm are obtained.

10) Age >/= 18

11) World Health Organization (WHO) Performance Status of </= 2

12) Life expectancy of >/= 12 weeks

13) Patients must have the following laboratory values: • Absolute Neutrophil Count (ANC) >/= 1.5 x 10^9/L • Hemoglobin (Hgb) >/= 9 g/dl • Platelets (plt) >/= 100 x 10^9/L • Potassium within normal limits or correctable • Total calcium (corrected for serum albumin) within normal limits or correctable • Magnesium >/= the lower limit of normal or correctable • Phosphorus >/= the lower limit of normal or correctable. Continued in Inclusion #14

14) AST/SGOT and ALT/SGPT </= 2.5 x Upper Limit of Normal (ULN) or </= 5.0 x ULN if liver metastases are present • Serum bilirubin </= 1.5 x ULN • Serum creatinine </= 1.5 x ULN or 24-hour clearance >/= 50 mL/min. Continued in Inclusion #15

15) Negative serum pregnancy test within 48 hours before starting study treatment in women with childbearing potential

16) Able to sign informed consent and to comply with the protocol

Exclusion Criteria:

1) Patients who have signs/symptoms attributable to brain metastases and have not been assessed with radiologic imaging to rule out the presence of brain metastases

2) Fulminant disease

3) Prior treatment with a PI3K inhibitor

4) Lytic bone metastasis if the sole lesion of the patient is a bone metastasis

5) Acute or chronic liver disease or renal disease

6) Acute or chronic pancreatitis

7) Patients with any peripheral neuropathy >/= CTCAE grade 2

8) Patients with unresolved diarrhea >/= CTCAE grade 2

9) Any of the following concurrent severe and/or uncontrolled medical conditions which could compromise participation in the study: • Impaired cardiac function or clinically significant cardiac diseases, including any of the following: 1. LVEF < 45% as determined by MUGA scan or ECHO 2. Complete left bundle branch block 3. ST depression or elevation of >/= 1.5 mm in 2 or more leads 4. Congenital long QT syndrome 5. History or presence of ventricular arrhythmias or atrial fibrillation 6. Clinically significant resting bradycardia (< 50 beats per minute) Continued in Exclusion #10.

10) 7. QTc > 460 msec on screening ECG 8. Right bundle branch block + left anterior hemiblock (bifascicular block) 9. Unstable angina pectoris </= 3 months prior to starting the study drug 10. Acute myocardial infarction </= 3 months prior to starting the study drug 11. Other clinically significant heart disease such as congestive heart failure requiring treatment or uncontrolled hypertension. Continued in Exclusion #11.

11) Patients with diabetes mellitus requiring insulin treatment, history of gestational diabetes mellitus, patients with known coagulopathies, other concurrent severe and/or uncontrolled concomitant medical conditions (e.g. active or uncontrolled infection) that could cause unacceptable safety risks or compromise compliance with the protocol

12) Patients with a history of photosensitivity reactions to other drugs

13) Any of the following ophthalmological findings: • Progressive eye disease that could lead to severe loss of visual acuity or visual field loss during the study period • Inability to perform the ophthalmic procedures required in this protocol

14) Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of BEZ235 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection). Patients with unresolved diarrhea will be excluded as previously indicated

15) Patients who have been treated with any hematopoietic colony-stimulating growth factors (e.g., G-CSF, GM-CSF) </= 2 weeks prior to starting study drug. Erythropoietin or darbepoetin therapy, if initiated before enrollment, may be continued

16) Patients who are currently receiving treatment with medication that has the potential to prolong the QT interval or inducing Torsades de Pointes, and the treatment cannot either be discontinued or switched to a different medication prior to starting study drug

17) Patients who are currently receiving treatment with therapeutic doses of warfarin sodium (Coumadin®)

18) Patients who have received chemotherapy, immunotherapy (except for trastuzumab) or investigational drugs </= 4 weeks prior to starting study drug or who have not recovered from side effects of such therapy

19) Patients who have received any continuous-dosing (i.e. daily dosing, ever-other-day dosing, Monday-Wednesday-Friday dosing weekly etc) therapeutic modalities or investigational drug (excluding monoclonal antibodies) </= 5 half lives prior to starting study drug or who have not recovered from side effects of such therapy

20) Patients who have received corticosteroids </= 2 weeks prior to starting study drug or who have not recovered from the side effects of such treatment

21) Patients who have received wide field radiotherapy </= 4 weeks or limited field radiation for palliation </= 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy. For breast cancer patients, the site of radiotherapy should not be the only site of measurable disease unless there is evidence of disease progression at this site prior to entry on this study

22) Patients who have undergone major surgery </= 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy

23) Women of child-bearing potential who are pregnant or breast feeding or adults of reproductive potential not employing an effective method of birth control. Barrier contraceptives must be used throughout the trial in both sexes. Continued in Inclusion #24

24) Women of child-bearing potential, defined as sexually mature women who have not undergone a hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive months (i.e., who has had menses any time in the preceding 12 consecutive months), must have a negative serum pregnancy test </= 48 hours prior to starting BEZ235.

25) Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory)

26) Patients with a history of another primary malignancy that is currently clinically significant, has potential for metastases or currently requires active intervention

27) Blood pressure of > 140/90 mmHg.

Links

Registration Number: NCT00620594
Study Information on Clinical Trials Registry (clinicaltrials.gov)