Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Also known as BEZ235
BEZ235+ Trastuzumab Phase l/Phase ll · 6 trials · 9 indications
PFS rate at 16 weeks was defined as a binary variable. Patients were considered as 'progression free' after 16 weeks if they had an overall lesion response of complete response (CR) partial response ('PR) or stable disease (SD)' and "progressed" if they had an overall lesion response of 'Progressive disease (PD) at the scan which occurred on day 105 after start of treatment, or later. Patients whose 16 weeks tumor assessment was unknown, missing or outside the window was not considered as 'progression free' and was considered a "failure" and counted only in the denominator for the estimation of the 16 week progression free rate.
Dose escalation part: Determine MTD and /or RDE of the combinations abiraterone acetate + BEZ235 and abiraterone acetate + BKM120 by assessing the incidence of DLTs in cycle 1
Dose expansion part: Assess anti-tumor activity of the combinations (abiraterone acetate + BEZ235 and abiraterone acetate + BKM120) in castration-resistant prostate cancer patients with abiraterone acetate failure as on treatment PSA progression according to prostate cancer working group criteria 2 (PCWG2) by assessing PSA decline ≥ 30% at Week 12 or later.
DLT is defined as treatment-related toxicity (classified according Common Toxicity Criteria for Adverse Events (CTCAE) Version 4) occurring during the first 28 treatment days and meeting specific protocol-predefined criteria. The information will be integrated in a Bayesian logistic regression model with overdose control to estimate the maximum tolerated dose (MTD)
PFS is defined as the time from randomization until objective tumor progression or death from any cause. Radiological assessments will be performed every 6 weeks for the first 36 weeks after treatment start, then every 12 weeks.
| Arm | Type | Description |
|---|---|---|
| BEZ235 300 mg/400 mg bid (Stage 1) | EXPERIMENTAL | Stage 1 consisted of a single arm where patients received BEZ235 300mg or 400mg bid. Initially the study started with a dose of 400mg bid. However, following an amendment after the preliminary safety and tolerability data from the first 3 patients treated at the 400mg dose, the dosage was changed to 300mg bid. |
| Dose escalation: BEZ235 + Zytiga® | EXPERIMENTAL | BEZ235 oral twice daily: 200 mg, 300 mg, and 400 mg dose levels to be tested in the dose escalation part in combination with abiraterone acetate Zytiga® abiraterone acetate oral once daily: 1000 mg taken with low dose prednisone as per the label |
| Dose escalation: BKM120 + Zytiga® | EXPERIMENTAL | BKM120 oral once daily: 60 mg, 80 mg and 100 mg dose levels to be tested in the dose escalation part in combination with abiraterone acetate Zytiga® abiraterone acetate oral once daily: 1000 mg taken with low dose prednisone as per the label |
| Dose expansion: BEZ235 + Zytiga® | EXPERIMENTAL | BEZ235 oral twice daily: 200 mg, 300 mg, and 400 mg dose levels to be tested in the dose escalation part in combination with abiraterone acetate Zytiga® abiraterone acetate oral once daily: 1000 mg taken with low dose prednisone as per the label |
| Dose Expansion: BKM120 + Zytiga® | EXPERIMENTAL | BKM120 oral once daily: 60 mg, 80 mg and 100 mg dose levels to be tested in the dose escalation part in combination with abiraterone acetate Zytiga® abiraterone acetate oral once daily: 1000 mg taken with low dose prednisone as per the label |
| BEZ235 + Trastuzumab (Phase l /Phase ll) | EXPERIMENTAL | Phase l: Eligible patients will receive increasing doses of oral BEZ235 administered on a continuous twice daily (BID) schedule + weekly trastuzumab at a fixed dose of 2 mg/kg. Treatment will be organized into cycles of 28 days. Phase ll: Eligible patients will receive weekly trastuzumab (2 mg/kg) + oral BEZ235 on a continuous twice daily (BID schedule) at the MTD or RP2D. Treatment will be organized into cycles of 21 days. |
| Lapatinib + Capecitabine (Phase II) | ACTIVE_COMPARATOR | Eligible patients will receive lapatinib (1250 mg given orally once daily on days 1 through 21) in combination with capecitabine (2000 mg/m2/day administered orally in 2 doses approximately 12 hours apart on days 1 through 14). Treatment will be organized into cycles of 21 days . |
| BEZ235 + paclitaxel | EXPERIMENTAL | - |
| BKM120 + paclitaxel | EXPERIMENTAL | - |
| BEZ235 + paclitaxel + trastuzumab | EXPERIMENTAL | - |
| BKM120 + paclitaxel + trastuzumab | EXPERIMENTAL | - |
| BEZ235 Dose Escalation once daily | EXPERIMENTAL | oral BEZ235 once daily (q.d.) |
| BEZ Dose escalation twice daily | EXPERIMENTAL | oral BEZ235 twice daily (b.i.d.) |
| BEZ235 Alone, Dose Escalation | EXPERIMENTAL | - |
| BEZ235 + trastuzumab, Dose Escalation | EXPERIMENTAL | - |
| BEZ235 Alone, MTD Expansion | EXPERIMENTAL | - |
| BEZ235 + Trastuzumab, MTD Expansion | EXPERIMENTAL | - |
| Name | Type | Description |
|---|---|---|
| BEZ235 (Stage 1) | DRUG | The investigational study drug used in this trial was BEZ235, which was supplied as 50mg, 200mg, 300mg, and 400mg solid dispersion sachets. Supply as 200mg and 50mg were provided for dose reduction. Patients were instructed to take the contents of one sachet of BEZ235 twice a day in the morning within 30 minutes after a light meal (breakfast). |
| BEZ235 | DRUG | BEZ235 will be supplied as 50mg, 100mg, 200mg, 300mg and 400mg SDS sachets. At each patient's visit, patient will reecive a prescription of an adequate drug supply for self administration at home. |
| BKM120 | DRUG | BKM120 will be supplied as 10mg and 50mg hard gelatin capsules. At each patient's visit, patient will reecive a prescription of an adequate drug supply for self administration at home. |
| BEZ235 + Trastuzumab Phase l/Phase ll) | DRUG | Phase l: Patients will receive increasing doses of oral BEZ235 (BID) together with standard weekly trastuzumab at a fixed dose. BEZ235 doses will be escalated in cohorts of 3 to 6 patients guided by an adaptive Bayesian logistic regression model with overdose control until MTD/RP2D has been established. Phase ll: If randomized to the trastuzumab + BEZ235 arm, patients will receive standard weekly trastuzumab in combination with oral BEZ235 (BID) at the MTD or RP2D and will continue on study treatment until PD, unacceptable toxicity or until other pre-defined discontinuation criteria are met. They will have regular safety assessments and will be evaluated for response to treatment according to RECIST every 2 cycles for the first 36 weeks then every 12 weeks until disease progression (or start of new anti-neoplastic therapy). |
| Lapatinib + Capecitabine (Phase II) | DRUG | If randomized to the lapatinib + capecitabine treatment arm, patients will receive standard lapatinib plus capecitabine until PD, unacceptable toxicity or until other pre-defined discontinuation criteria are met. Patients will have regular safety assessments and will be evaluated for response to treatment according to RECIST every 2 cycles for the first 36 weeks then every 12 weeks until disease progression (or start of new anti-neoplastic therapy). After progression, survival f-up will continue. All patients participating in the Phase II part of the study will be required to have available archival or fresh tumor tissue for biomarker analysis prior to treatment start |
| BEZ235 + paclitaxel | DRUG | - |
| BKM120 + paclitaxel | DRUG | - |
| BEZ235 + paclitaxel + trastuzumab | DRUG | - |
| BKM120 + paclitaxel + trastuzumab | DRUG | - |
Inclusion Criteria: * Unresectable or metastatic, histologically confirmed low or intermediate grade pancreatic neuroendocrine tumor with radiological evidence of disease progression since last treatment * Refractory disease to treatment with mTOR inhibitor * Measurable disease per RECIST Version 1...
BEZ235 + Trastuzumab Phase I/Phase II refers to a clinical study combining the small molecule BEZ235 with trastuzumab in patients with HER2-positive breast cancer who had failed prior trastuzumab treatment. The trial, NCT01471847, was a Phase Ib/II study conducted in Spain and the United Kingdom and is now completed.
BEZ235 has been studied in advanced solid tumors, breast cancer, castration-resistant prostate cancer, locally advanced breast cancer, metastatic or locally advanced solid tumors, and pancreatic neuroendocrine tumors. These are investigational uses in clinical trials, not approved indications. The studies were run in patients with these cancer types, including some who had failed prior therapies.
BEZ235 is developed by Novartis AG, which trades under the ticker NVS. Novartis sponsored the clinical trials evaluating BEZ235 both as a single agent and in combinations, including with trastuzumab, paclitaxel, abiraterone acetate, and BKM120, across several cancer indications.
BEZ235 is investigational and has been tested in Phase 1 and Phase 2 clinical trials. The program includes a Phase II trial in pancreatic neuroendocrine tumors and Phase Ib or Phase Ib/II studies in castration-resistant prostate cancer, HER2-positive breast cancer, and advanced solid tumors. All listed trials are completed.
BEZ235 has been evaluated in completed trials including NCT01658436, a Phase II study in advanced pancreatic neuroendocrine tumors after mTOR inhibitor failure; NCT01634061, a Phase Ib study with abiraterone acetate in castration-resistant prostate cancer; NCT01471847, a Phase Ib/II study with trastuzumab in HER2-positive breast cancer; and NCT01285466, a Phase I study with paclitaxel with or without trastuzumab in solid tumors.