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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 has several 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.

In patients with metastatic breast cancer (MBC), tesetaxel was shown to have significant, single-agent antitumor activity in two multicenter, Phase 2 studies. Tesetaxel currently is the subject of three studies in breast cancer, including a multinational, multicenter, randomized, Phase 3 study in patients with MBC, known as CONTESSA (clinicaltrials.gov). Positive results of CONTESSA were recently presented at the 2020 San Antonio Breast Cancer Symposium (SABCS). We plan to submit a New Drug Application for tesetaxel to the U.S. Food and Drug Administration (FDA) in mid-2021. 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), 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:

  • Not be substantially effluxed by the P-glycoprotein (P-gp) pump, with the intent of retaining activity against chemotherapy-resistant tumor cells;

  • Have high oral bioavailability;

  • Have high solubility; and

  • Have a long t1/2 in humans.

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.

Tesetaxel has exhibited potent antitumor activity in in vitro nonclinical studies, with an overall GI₅₀ 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. 

 

CLINICAL STUDIES

More than 1,200 patients have been treated with tesetaxel in 29 clinical studies. Tesetaxel was administered as monotherapy in 21 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 solid tumors 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 hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative 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). 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 (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).

Adverse Event Profile

The adverse event profile of 187 patients treated with tesetaxel monotherapy at 27 mg/m² once every three weeks (Q3W) 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.

CONTESSA

In CONTESSA, 685 patients with HR-positive, HER2-negative MBC were randomized to receive either tesetaxel dosed orally at 27 mg/m² on the first day of a 21-day cycle plus a reduced dose of capecitabine (1,650 mg/m²/day dosed orally for 14 days of a 21-day cycle) or the approved dose of capecitabine alone (2,500 mg/m²/day dosed orally for 14 days of a 21-day cycle).

  • Primary endpoint

    • PFS as assessed by the Independent Radiologic Review Committee (IRC)

    • 90% power to detect a hazard ratio of 0.71 (median PFS difference of 2.5 months)

  • Secondary endpoints

    • Overall survival (OS)

    • ORR as assessed by IRC (in patients with measurable disease)

    • Disease control rate (DCR) [ORR or stable disease of ≥24 weeks] as assessed by IRC (in patients with measurable disease)

 

685 patients were enrolled in CONTESSA, including 45% in North America, 37% in Europe and 18% in Asia‑Pacific. 100% of patients had previously received a taxane, approximately 86% had previously received an anthracycline and approximately 50% had previously received a cyclin-dependent kinase (CDK) 4/6 inhibitor. Approximately 80% of patients had visceral disease.

CONTESSA met the primary endpoint of improved PFS as assessed by the IRC. Median PFS was 9.8 months for tesetaxel plus a reduced dose of capecitabine vs. 6.9 months for the approved dose of capecitabine alone, an improvement of 2.9 months. The risk of disease progression or death was reduced by 28.4% [hazard ratio=0.716 (95% confidence interval [CI]: 0.573-0.895); p=0.003] for tesetaxel plus a reduced dose of capecitabine vs. the approved dose of capecitabine alone.

The treatment effect was similar across protocol-specified subgroups, including patients who had rapid disease recurrence following neoadjuvant or adjuvant taxane therapy, patients who had been previously treated with a CDK 4/6 inhibitor and patients in each geographic region.

ORR by IRC and DCR by IRC were significantly higher for tesetaxel plus a reduced dose of capecitabine vs. the approved dose of capecitabine alone.

The most common Grade ≥3 TEAE associated with tesetaxel plus capecitabine was neutropenia. The most common Grade ≥3 TEAE associated with capecitabine alone was hand-foot syndrome. Rates of Grade ≥3 neuropathy and Grade 2 alopecia (hair loss) were low. There were no treatment-related hypersensitivity reactions.

Treatment discontinuation due to any adverse event occurred in 23.1% of patients treated with tesetaxel plus capecitabine vs. 11.9% of patients treated with capecitabine alone.

The relative delivered dose intensity, which accounts for not only the frequency, but also the magnitude of reductions and treatment adherence, was higher in patients treated with tesetaxel plus capecitabine.

 

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 a 21-day cycle plus a reduced dose of capecitabine (1,650 mg/m²/day dosed orally for 14 days of a 21-day cycle) in 149 patients with HR-positive, HER2-negative 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 DoR as assessed by the IRC, PFS as assessed by the IRC, DCR as assessed by the IRC and OS.

 

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 200 patients with triple-negative MBC 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 a 21-day cycle plus either: (1) nivolumab at 360 mg by intravenous (IV) infusion on the first day of a 21-day cycle; (2) pembrolizumab at 200 mg by IV infusion on the first day of a 21-day cycle; or (3) atezolizumab at 1,200 mg by IV infusion on the first day of a 21-day cycle. Nivolumab and pembrolizumab (programmed cell death protein 1 [PD-1] inhibitors) and atezolizumab (a programmed death-ligand 1 [PD-L1] inhibitor) are immuno-oncology (IO) agents approved for the treatment of multiple types of cancer. Two of these agents, atezolizumab and pembrolizumab, have been approved by the FDA as a first-line treatment for patients with triple-negative MBC. The primary endpoints for Cohort 1 are ORR and PFS in patients with PD-L1 positive status. The secondary endpoints are ORR and PFS in all patients, 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 60 elderly patients with HER2-negative MBC who have not received prior chemotherapy for advanced disease will receive tesetaxel monotherapy dosed orally at 27 mg/m² on the first day of a 21-day cycle. The primary endpoints for Cohort 2 are ORR and PFS in patients with hormone receptor-positive, HER2-negative disease. The secondary endpoints are ORR and PFS in patients with triple-negative disease, DoR and OS.

• In Cohort 3, approximately 60 non-elderly adult patients with HER2-negative MBC who have not received prior chemotherapy for advanced disease will receive tesetaxel monotherapy dosed orally at 27 mg/m² on the first day of a 21-day cycle. The primary endpoints for Cohort 3 are ORR and PFS in patients with hormone receptor-positive, HER2-negative disease. The secondary endpoints are ORR and PFS in patients with triple-negative disease, DoR and OS.

Expanded Access Policy

Thank you for your interest in our expanded access policy. Expanded access requests for our investigational drug, tesetaxel, will be evaluated on a case-by-case basis and must meet the following criteria:

  • The request is made by a patient’s treating physician, who is properly licensed and fully qualified to administer tesetaxel;

  • The treating physician is willing to comply with regulatory requirements, including Title 21, Code of Federal Regulations Part 312, Subpart I – Expanded Access to Investigational Drugs for Treatment Use, including the requirement for an individual patient expanded access investigational new drug application;

  • The treating physician is willing to comply with all applicable legal requirements of the relevant jurisdiction and any additional requirements established by Odonate, which may include safety reporting and other requirements;

  • The patient to be treated must have a serious or immediately life-threatening disease or condition, and there is no comparable or satisfactory alternative therapy;

  • The potential patient benefit justifies the potential risks of the treatment, and those potential risks are not unreasonable in the context of the disease or condition to be treated;

  • Providing the investigational drug for the requested use will not interfere with the initiation, conduct or completion of clinical investigations that could support marketing approval of the investigational drug for the expanded access use; and

  • The patient cannot obtain the investigational drug under another IND or protocol.

If you have a request for expanded access that meets these criteria, please submit it to expandedaccess@odonate.com. We anticipate acknowledging receipt of your request within 5 days and will endeavor to respond to your request as quickly as possible.

 

Our posting of this policy and evaluation of an expanded access request do not guarantee that access to tesetaxel will be provided. We reserve the right to decline a request for expanded access.

 

When applicable, this website will be updated with hyperlinks to the relevant expanded access records on www.clinicaltrials.gov after such records become active. In accordance with the 21st Century Cures Act, we may revise this policy at any time.

 

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

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