Roche trials database

Protocol number:

NP22002

Title of Study:

An exploratory study to evaluate the biological activity of RG1507, a human monoclonal antibody antagonist of the insulin-like growth factor receptor (IGF-1R) in women with operable breast cancer

Sponsor:

Hoffmann-La Roche

Company division:

Pharmaceutical

Product name:

RG1507

Generic name:

RG1507

Therapeutic area:

• Breast Cancer

Clinical study summary:

This single-arm, open-label study was designed to evaluate the biological activity if RG1507 in patients with operable breast cancer. The study was terminated before completion of study part 1.

Study center(s):

Single center in United Kingdom

Phase of development:

I

Objectives:

The primary objectives were to evaluate the effect of RG1507 treatment on IGF-1R expression in breast cancer cells (Study part 1), and to define and confirm a pharmacokinetic/pharmacodynamics (PK/PD) threshold effect of RG1507 by assessing lower dose levels (Study part 2, not conducted).

The secondary objectives were to evaluate the effect of RG1507 treatment in breast cancer cells on p-AKT level, on Ki67 index, on apoptotic index; to correlate RG1507 PK parameters in serum with biologic changes in tumor tissue, to evaluate the safety and tolerability of RG1507 in patients with breast cancer.

Methodology:

The study consisted of a screening visit a baseline visit a 4-week treatment phase (a single RG1507 16 mg/kg IV dose on day 1 and definitive breast surgery 8 days later) and a follow-up visit (up to 30 days after the single dose of RG1507).

Prior to dosing on day 1, a physical examination was performed and blood samples for hematology, biochemistry, coagulation, PK/PD, and PBMC samples were collected. Vital signs were assessed prior to and during administration of RG1507. Each patient was maintained in observation after RG1507 infusion. As part of the standard of care, after identification of a suspicious breast lesion, each patient must have undergone a diagnostic biopsy and have 2 samples available for submission, one fresh frozen biopsy specimen and one specimen embedded in paraffin. After confirmation of the diagnosis and provision of informed consent, study specific procedures would be conducted. In patients who consented to this optional procedure, prior to, or on, study day 1, an approximately 2 mm punch biopsy was taken from the affected breast skin of each patient who consented to this optional procedure. Patients were then treated with a single dose of RG1507. On study day 8, breast cancer tissue samples were collected from the affected breast during surgery and a skin biopsy was taken from the skin overlying the operated/affected breast. The breast and skin tissue samples were used for study-specific biomarker analyses.

An interim analysis was planned after 15 patients had been enrolled but was not performed because the study was terminated before reaching this number of patients. Breast tissue samples were evaluated for IGF-1R levels before and after one RG1507 dose by immunohistochemistry. If sufficient biologic effect of RG1507 (down-regulation) had been demonstrated in study part 1, three additional treatments would have been dosed in part 2. All patients were followed for 30 days after the single RG1507 dose for safety monitoring and blood sampling.

Number of patients (planned/analyzed):

40 patients planned; 8 patients analyzed

Diagnosis and main criteria for inclusion:

Female patients ≥ 18 years of age with a histological diagnosis of invasive, operable breast cancer and available liquid nitrogen-stored breast tissue samples from previous standard-of care breast cancer diagnostic biopsy. Patients were also required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

Test product, dose and mode of administration or test procedure:

In part 1 of the study, a single dose of RG1507 16 mg/kg was given intravenously (IV). In part 2 of the study (not conducted), a single dose of RG1507 9 mg/kg, 3 mg/kg or 1 mg/kg was to be given IV.

Duration of treatment:

Single dose study

Reference therapy, dose and mode of administration or reference procedure:

N/A

Criteria for evaluation (efficacy, safety):

Pharmacodynamics: PD assessments included analysis of serum and tumor biopsy samples for biomarkers potentially related to IGF signaling. In addition, blood and skin samples were taken before RG1507 administration and at the time of breast surgery skin sample was optional prior to RG1507 administration); these were analyzed for the same biomarkers as the tumor tissues.

Safety: Adverse events (AEs), clinical laboratory tests, vital signs, 12-lead electrocardiograms, chest X-ray, physical examination.

Statistical methods:

Due to the study termination, the planned statistical analysis of the primary and secondary variables was not conducted. Descriptive statistics were used to analyze all safety data.

Summary (efficacy, safety, other results):

Demographics:

All 8 women included in the trial were white, with ages ranging from 46 to 70 years. All patients had a stage IIA ductal tumor.

Analysis Populations:

All 8 patients enrolled were included in the safety population. Due to the early termination of the trial, only limited PD and PK analyses were performed.

Pharnacodynamics:

Three biomarkers, IGF1R, pAKT and Ki-67, defined in the primary and part of secondary objectives of the study were assessed by immunohistochemistry on the diagnostic and surgery samples. All 8 patients expressed high to very high levels of IGF1R on the cell membrane (H score between 105 to 290) and in cytoplasma (H score 70-205). On day 6, after one dose of RG1507 (16 mg/kg IV), 6 out of 8 patients showed a slight numerical down-regulation of the membrane IGF1R level and up-regulation of the cytoplasmic IGF1R level. Although these dynamic changes are consistent with the expected directions, the magnitude is insignificant and within the error of semi-quantitative measurement of the immunohistochemistry assay.

Six out of 8 patients showed very high nuclear pAKT levels (H score 230-300) and essentially no difference between pre- and post treatment measurements. Only one patient with more moderate predosing nuclear pAKT level showed a drastic decrease (by 2.5 fold). Relatively large decrease in Ki-67 expression was observed only in patient number 1 (~30%) and large increase in patient number 2 (~80%). All other patients showed smaller changes in either direction.

Safety:

Eight patients received a single dose of RG1507 of 16 mg/kg corresponding to absolute doses of between 850 mg and 1338 mg.

Thirty-five AEs were reported by the 8 patients included in the study. Procedural complications, of which most were incision site pain were the most commonly reported events (13 events, of which 7 were incision site pain). Reproductive system and breast disorders (6 events, of which 2 were amenorrhea), were the next most commonly reported. Less than 5 AEs were reported in each of the other body systems. All AEs were classified as mild or moderate in intensity. The relationship was considered as probable for 1 event (vessel puncture site hematoma) and possible for 5 events in 4 patients (all reproductive system and breast disorders)

There were no deaths. There were 2 serious adverse events (SAEs) in one patient (sensory disturbance and peripheral coldness). The causal relationship was considered to be remote for both events, which presented after surgery. The events were unresolved at the unscheduled last study visit.

Three shifts were reported-two from grade 0 to grade 1 (lymphocytes and ALAT) and one from grade 0 to grade 3 (international normalized ratio, INR) in one patient at the follow-up visit. The grade 3 INR was not associated with any other issues and was not reported as an adverse event.

Instances of high and low diastolic BP, high systolic BP and high and low heart rate were reported in all patients throughout the study. Some of the patients had abnormalities at screening and there was no clear temporal relationship with administration of study drug. There were no reports of abnormal ECGs (after screening, ECGs were only performed if clinically indicated).

Enrollment in the study was discontinued based on Sponsor decision to stop development of the compound, and was not due to safety reasons. The study was discontinued before completion of enrollment into part 1 or initiation of part 2.

Conclusions:

Due to the termination of the study and the resulting small patient number, no definite conclusions can be made regarding the objectives of the study.

Date of report:

01.01.2011

Click here for the protocol registry listing of this trial.