Odonate Therapeutics

NOW ENROLLING

More information >

 

TESETAXEL

Tesetaxel is an investigational, orally administered chemotherapy agent that belongs to a class of drugs known as taxanes, which are widely used in the treatment of cancer. Tesetaxel is an investigational product, and its safety and efficacy have not been established by any agency. Tesetaxel has several pharmacologic properties that make it unique among taxanes, including: oral administration with a low pill burden; a long (~8-day) terminal plasma half-life ("t1/2") in humans, enabling the maintenance of adequate drug levels with relatively infrequent dosing; no history of hypersensitivity (allergic) reactions; and significant activity against chemotherapy-resistant tumors. More than 1,000 patients have been treated with tesetaxel in clinical studies. In patients with metastatic breast cancer (“MBC”), tesetaxel was shown to have significant, single-agent antitumor activity in two multicenter, Phase 2 studies. In December 2017, Odonate initiated CONTESSA, a multinational, multicenter, randomized, Phase 3 study of tesetaxel in patients with locally advanced or metastatic breast cancer (clinicaltrials.gov). Our goal for tesetaxel is to develop an effective chemotherapy choice for patients that provides quality-of-life advantages over current alternatives.

 

Tesetaxel, which we believe will qualify as a New Chemical Entity (“NCE”) if and when a New Drug Application (“NDA”) is submitted, retains the same taxane core as the approved taxanes, but includes the addition of two novel, nitrogen-containing functional groups. Tesetaxel is chemically designed to: (i) not be substantially effluxed by the P-glycoprotein (“P-gp”) pump, with the intent of retaining activity against chemotherapy-resistant tumor cells; (ii) have high oral bioavailability; (iii) have high solubility; and (iv) have a long (~8 day) t1/2 in humans. The table below includes the chemical and pharmacologic properties of paclitaxel, docetaxel and tesetaxel.

We believe the improved pharmacologic properties of tesetaxel enable a simple, patient-friendly dosing regimen, as shown in the following table.

Tesetaxel is chemically designed to have a long (~8 day) t1/2 in humans (see following figure), which may allow adequate drug levels to be maintained with relatively infrequent dosing.

We believe that tesetaxel’s unique properties may translate into significant benefits for patients. These may include:


• Oral administration with a low pill burden;


• The maintenance of adequate drug levels with relatively infrequent dosing, enabled by a long (~8-day) t1/2 in humans;


• No history of hypersensitivity reactions; and


• Significant activity against chemotherapy-resistant tumors.

 

NONCLINICAL STUDIES

Tesetaxel has exhibited potent antitumor activity in both in vitro (in a test tube) and in vivo (in a live organism) nonclinical studies (Shionoya et al, Cancer Science 2003;94(5):459-466). Tesetaxel retains potent antitumor activity against chemotherapy-resistant tumor cells, including tumor cells over-expressing the P-gp efflux pump. A defense mechanism of tumor cells, this efflux pump functions to expel toxins, including many chemotherapy agents.

In Vitro Antitumor Activity

Tesetaxel has exhibited potent antitumor activity in in vitro nonclinical studies, with an overall GI₅₀ (the concentration of drug required to inhibit growth by 50%) of less than 1 nM. GI₅₀ is a commonly used nonclinical measurement of antitumor potency; lower GI₅₀ numbers connote higher potency (1 nM is 1/1,000th of 1 µM). In human tumor cell lines, tesetaxel largely retained antitumor cytotoxic (cell-killing) potency against taxane-resistant (P-gp positive) and other chemotherapy-resistant tumors, while paclitaxel and docetaxel lost considerable antitumor potency (Shionoya et al, Cancer Science 2003;94(5):459-466). Consistent with this finding, the uptake and accumulation of tesetaxel in both P-gp negative and P-gp positive tumor cells were greater than that of either paclitaxel or docetaxel. The relative loss of cytotoxic potency between P-gp negative and P-gp positive tumor cells for paclitaxel, docetaxel and tesetaxel is shown in the following table (low numbers connote high potency, and high numbers connote low potency).

 

CLINICAL STUDIES

More than 1,000 patients have been treated with tesetaxel across 25 clinical studies. Tesetaxel has been administered as monotherapy in 17 studies and in combination with other agents in 8 studies. Studies have been completed in MBC, gastric cancer, colorectal cancer, non-small cell lung cancer and other cancers as first-line, second-line or salvage therapy.

The results from a Phase 2 clinical study of tesetaxel monotherapy in MBC (TOB203) are summarized below.

 

Study TOB203: A Phase 2 Study of Tesetaxel as First-line Chemotherapy for MBC

In Study TOB203, 38 patients with human epidermal growth factor receptor 2 ("HER2") negative, hormone receptor ("HR") positive MBC received tesetaxel orally as a single agent once every three weeks at a starting dose of 27 mg/m². Objective response rate (“ORR”) based on Response Evaluation Criteria in Solid Tumors ("RECIST") 1.1 was the primary endpoint (Seidman et al., 2018 ASCO Annual Meeting).

 

Median age was 58 years (range: 36-80 years). Eighty-seven percent (87%) had visceral disease, 74% previously received at least one endocrine therapy, 68% previously received neoadjuvant or adjuvant chemotherapy and 53% previously received a taxane-containing regimen. The figures that follow show the study design and patient characteristics (Seidman et al., 2018 ASCO Annual Meeting).

Exposure and Patient Characteristics

ECOG=Eastern Cooperative Oncology Group

In all 38 patients, the confirmed response rate was 45%. The confirmed response rate was consistent across subgroups. Forty-four percent (44%) of patients who did not previously receive a taxane-containing regimen achieved a confirmed response, compared to 45% of patients who previously received a taxane-containing regimen. Median duration of response ("DoR") was 10.9 months, and median progression-free survival ("PFS") was 5.4 months (Seidman et al., 2018 ASCO Annual Meeting).

Tumor change from baseline in target lesions by individual patient is shown in the following figure.

Patient response is shown in the following figure.

Patient response by prior taxane exposure is shown in the following figure.

Adverse Event Profile

Tesetaxel, administered both alone and in combination with capecitabine, has been generally well tolerated. In 8 studies (927A-PRT001, 927A-PRT004, 927E-PRT003, 927E-PRT005, 927E-PRT007, 927A-PRT006, TOST107 and TOST107XT), a total of 187 patients were treated with tesetaxel at 27 mg/m² once every three weeks as monotherapy (N=156) or in combination with capecitabine at 1,750-2,500 mg/m² (N=31). 

A summary of tesetaxel’s adverse event profile based on these studies is shown in the following table.

Ongoing Clinical Studies

We are currently conducting three clinical studies in breast cancer, including CONTESSA, a multinational, multicenter, randomized Phase 3 study of tesetaxel in patients with MBC, as shown in the following table.

CONTESSA

CONTESSA is a multinational, multicenter, randomized, Phase 3 study of tesetaxel, an investigational, orally administered taxane, in patients with MBC. CONTESSA is comparing tesetaxel dosed orally at 27 mg/m² on the first day of each 21-day cycle plus a reduced dose of capecitabine (1,650 mg/m²/day dosed orally for 14 days of each 21-day cycle) to the approved dose of capecitabine alone (2,500 mg/m²/day dosed orally for 14 days of each 21-day cycle) in approximately 600 patients randomized 1:1 with HER2 negative, HR positive MBC previously treated with a taxane in the neoadjuvant (prior to surgery) or adjuvant (immediately following surgery) setting. Capecitabine is an oral chemotherapy agent that is considered a standard-of-care treatment in MBC. Where indicated, patients must have received endocrine therapy with or without a cyclin-dependent kinase (“CDK”) 4/6 inhibitor. Patients with central nervous system (“CNS”) metastases are eligible. The primary endpoint is PFS as assessed by an Independent Radiologic Review Committee (“IRC”). The secondary efficacy endpoints are overall survival (“OS”), ORR as assessed by the IRC and disease control rate (“DCR”) as assessed by the IRC.

In June 2019, we announced that the Independent Data Monitoring Committee (the “IDMC”) for CONTESSA recommended that the study continue with no modifications following a planned interim efficacy futility analysis. The interim efficacy futility analysis was based on a pre-specified analysis of the first approximate 100 PFS events that occurred in the study. The purpose of the interim efficacy futility analysis was to facilitate the early termination of the study if the IDMC determined that achieving a positive outcome on the primary endpoint would be futile.

In October 2019, we announced that enrollment in CONTESSA was complete. We expect to report top-line results from CONTESSA in the third quarter of 2020.

BID=twice per day

In designing CONTESSA, we received non-binding advice from both the U.S. Food and Drug Administration (“FDA”) and the European Medicines Agency (“EMA”). We believe CONTESSA may serve as a single pivotal study sufficient for product registration, provided that the study demonstrates a statistically significant and clinically meaningful improvement in the primary endpoint, PFS, for tesetaxel plus a reduced dose of capecitabine as compared to the approved dose of capecitabine alone as well as an overall favorable benefit-risk profile for the tesetaxel plus a reduced dose of capecitabine regimen. Generally, a single pivotal study can be sufficient for FDA approval only when the study provides highly reliable and statistically strong evidence of an important clinical benefit and in which confirmation of the result in a second clinical trial would be practically or ethically impossible. There can be no assurance that the outcome of CONTESSA will be sufficient for the approval of tesetaxel by the FDA, European Commission or other regulatory agencies or that tesetaxel will be approved at all.

 

Registration studies of chemotherapy agents FDA-approved for advanced breast cancer are shown in the following table.

 

Reducing the Dose of Capecitabine in Combination with a Taxane

Clinical Studies Evaluating Lower Doses of Capecitabine Combined with a Taxane

Clinical studies support investigating the combination of a taxane with a reduced dose of capecitabine such as 1,650 mg/m²/day on the first 14 days of a 21-day cycle, the dose of capecitabine chosen for combination with tesetaxel in CONTESSA. In a review of 18 first-line MBC studies of taxane plus capecitabine combinations shown in the following table, there was no apparent dose response when comparing capecitabine at 1,650 mg/m²/day to capecitabine at 2,000 mg/m²/day (on the first 14 days of a 21-day cycle). Among these studies, the capecitabine 1,650 mg/m²/day dose was the most studied dose less than 2,000 mg/m²/day (5/8 studies). According to Lortholary, the trend toward improved efficacy with lower doses of capecitabine may result from the significantly lower proportion of patients discontinuing study therapy prematurely because of toxicity, and highlights the importance of administering capecitabine using a schedule that optimizes dose intensity and tolerability (Lortholary et alBreast Cancer Research and Treatment 2012;131:127-135).

Synergy when Combining a Taxane with Capecitabine in Nonclinical Studies

Nonclinical studies have shown synergy when combining a taxane with capecitabine. Taxanes up-regulate tumor levels of thymidine phosphorylase, the enzyme essential for the activation of capecitabine. These studies suggest the potential to reduce the dose of capecitabine without loss of efficacy. In two in vivo nonclinical studies of breast cancer, the combined administration of capecitabine and docetaxel resulted in antitumor efficacy significantly greater than the sum of the efficacy resulting from either agent administered as monotherapy (see the following figures). Furthermore, the synergy may be tumor-specific, as toxicity as measured by weight loss and effect on peripheral blood cells was minimal. 

In summary, we believe that the data support the investigation of tesetaxel at 27 mg/m² on the first day of a 21-day cycle plus capecitabine at 1,650 mg/m²/day on the first 14 days of a 21-day cycle as a novel, all-oral regimen with a potentially favorable benefit-risk profile for the treatment of patients with HER2 negative, HR positive MBC.

 

CONTESSA 2

CONTESSA 2 is a multinational, multicenter, Phase 2 study of tesetaxel, an investigational, orally administered taxane, in patients with MBC. CONTESSA 2 is investigating tesetaxel dosed orally at 27 mg/m² on the first day of each 21-day cycle plus a reduced dose of capecitabine (1,650 mg/m²/day dosed orally for 14 days of each 21-day cycle) in approximately 125 patients with HER2 negative, HR positive MBC not previously treated with a taxane. Capecitabine is an oral chemotherapy agent that is considered a standard-of-care treatment in MBC. Where indicated, patients must have received endocrine therapy with or without a CDK 4/6 inhibitor. Patients with CNS metastases are eligible. The primary endpoint is ORR as assessed by an IRC. The secondary efficacy endpoints are duration of response (“DoR”) as assessed by the IRC, PFS as assessed by the IRC, DCR as assessed by the IRC and OS.

CONTESSA 2 Study Design

 

CONTESSA TRIO

CONTESSA TRIO is a multi-cohort, multicenter, Phase 2 study of tesetaxel, an investigational, orally administered taxane, in patients with MBC.

• In Cohort 1, approximately 90 patients (with potential expansion to up to 150 patients) with locally advanced or metastatic triple-negative breast cancer (“TNBC”) who have not received prior chemotherapy for advanced disease will be randomized 1:1:1 to receive tesetaxel dosed orally at 27 mg/m² on the first day of each 21-day cycle plus either: (1) nivolumab at 360 mg by intravenous infusion on the first day of each 21-day cycle; (2) pembrolizumab at 200 mg by intravenous infusion on the first day of each 21-day cycle; or (3) atezolizumab at 1,200 mg by intravenous infusion on the first day of each 21-day cycle. Nivolumab and pembrolizumab (PD-1 inhibitors) and atezolizumab (a PD-L1 inhibitor) are immuno-oncology (“IO”) agents approved for the treatment of multiple types of cancer. One of these agents, atezolizumab, in combination with the intravenously delivered taxane, nab-paclitaxel, was recently approved by the U.S. Food and Drug Administration (“FDA”) as a first-line treatment for patients with metastatic TNBC. Patients with CNS metastases are eligible. The dual primary endpoints for Cohort 1 are ORR and PFS. Secondary endpoints include DoR and OS. Efficacy results for each of the three PD-(L)1 inhibitor combinations will be assessed for correlation with the results of each of the three approved PD-L1 diagnostic assays.

• In Cohort 2, approximately 40 elderly patients (with potential expansion to up to 60 patients) with HER2 negative MBC will receive tesetaxel monotherapy dosed orally at 27 mg/m² on the first day of each 21-day cycle. Patients with CNS metastases are eligible. The primary endpoint for Cohort 2 is ORR. Secondary endpoints include PFS, DoR and OS.

 

TESETAXEL PRESENTATIONS AND PUBLICATIONS

CONTESSA

CONTESSA 2

CONTESSA TRIO

TOB203

Tesetaxel: Activity of an Oral Taxane as 1st-Line Treatment in Metastatic Breast Cancer – Presented at the 2012 American Society of Clinical Oncology (ASCO) Annual Meeting

Tesetaxel, an Oral Taxane, as First-Line Therapy for Women with Metastatic Breast Cancer – Presented at the 2011 San Antonio Breast Cancer Symposium (SABCS)

927E-PRT005

Efficacy and Prediction of Response to the New Oral Taxane DJ-927 [Tesetaxel] in Anthracycline Pre-Treated Advanced Breast Cancer – Presented at the 2006 EORTC-NCI-AACR Molecular Targets and Cancer Therapeutics Symposium

TOST107

Phase 1B Study of an All-Oral Chemotherapy Regimen, Tesetaxel Plus Capecitabine, in Patients with Advanced Solid Tumors – Presented at the 2012 American Society of Clinical Oncology (ASCO) Annual Meeting

Preclinical

Tesetaxel, a novel, oral taxane, crosses intact blood-brain barrier (BBB) at therapeutically relevant concentrations – Presented at the American Association for Cancer Research (AACR) Annual Meeting 2019

Contact Us          Careers          Privacy Notice          Terms of Use

© 2020 Odonate Therapeutics, Inc.