Oral Taxane Shows Spunk in Metastatic Breast Cancer

CHICAGO – Tesetaxel, an investigational oral taxane, is highly active when used to treat chemotherapy-naive metastatic breast cancer, a phase II trial suggests. And in contrast to the main intravenously administered taxanes, it does not require steroidal premedication and can cause little-to-no peripheral neuropathy.

A total of 46 women were treated with tesetaxel just once every 3 weeks during an office visit in the trial. The overall response rate was 45% – at least a bit higher than the roughly 20%-35% previously seen with the intravenously administered taxanes paclitaxel (Taxol) and docetaxel (Taxotere), according to presenting author Dr. Loretta M. Itri.

"This compares favorably. This is a phase II open-label study. I’m sure the response rate is going to fall a little bit over time, but ... I think we are going to be nothing less than equivalent to the other taxanes," she said in an interview at the annual meeting of the American Society of Clinical Oncology.

A provision for dose escalation from 27 mg/m² to 35 mg/m² was halted halfway through the trial because there was minimal gain in efficacy but substantially more toxicity. "So this [27 mg/m²] is the dose that we will be taking forward in our clinical trials, and we are abandoning escalation," she said. There were no cases of hypersensitivity reaction regardless of dose used; the rate of grade 3 peripheral neuropathy was 16% with dose escalation but 0% without it.

The majority of the patients having progression on treatment had triple-negative disease, Dr. Itri noted. "Now that we know that it’s the triple-negatives who have recently received a taxane who are the ones who don’t respond, we will probably begin excluding that population ... so that we can further enrich [the study population]. We want to give the drug to people whom we can do something good for," she said.

The next step in breast cancer is an ongoing three-arm phase IIb trial comparing tesetaxel given every 3 weeks vs. weekly, and also comparing it with capecitabine (Xeloda), in about 200 patients.

"What’s interesting about the weekly dose is that we have seen in the phase I study no significant neutropenia. So we feel obligated to evaluate the weekly dose, because if we truly had a taxane regimen with no neutropenia, that could be important," said Dr. Itri, an oncologist and chief medical officer of Genta, the company that is developing tesetaxel.

"I will tell you that I have a real bias here ... The weekly dosing is going to really have to be something special for us to abandon the every-3-week dosing, because the convenience and the compliance are so easy," she continued. "These women have a life to live, and the drug was designed to be as user friendly as possible, and I personally don’t like the idea of sending patients home with cytotoxic chemotherapy."

Discussant Dr. Stacy L. Moulder of the University of Texas M.D. Anderson Cancer Center, Houston, noted the advantages of tesetaxel over intravenous taxanes with respect to factors such as oral administration, no need for premedication, and, possibly, reduced toxicity. "But the question that remains is, is this the best microtubule inhibitor?"

She pointed out that a trial of nab-paclitaxel (Abraxane) found approximately double the median duration of progression-free survival seen with tesetaxel in this trial and a fairly similar rate of higher-grade peripheral neuropathy (J. Clin. Oncol. 2009;27:3611-9). "So I think it remains unanswered whether this drug is as good as some of the currently existing novel taxanes," she maintained.

Unlike the intravenous taxanes, tesetaxel is not a substrate for P-glycoprotein (PGP), a transmembrane pump that is likely the main mechanism of taxane resistance, according to Dr. Itri. Thus, it is highly concentrated in cells that overexpress PGP. In preclinical studies, tesetaxel’s cytotoxic activity has been 3-10 times greater than that of the intravenous taxanes in cells not expressing PGP and 10-100 times greater in multidrug-resistant tumor cells overexpressing PGP.

Women were eligible for the trial if they had HER2-negative, chemotherapy-naive metastatic breast cancer. (Those with hormone receptor–positive disease could have received hormonal therapy for their metastases.) Prior adjuvant taxane therapy given more than a year before enrollment was permitted.

The women received single-agent tesetaxel orally once every 3 weeks and without any antiallergy premedication but with an oral antiemetic as a precaution. "We have completed an effect-of-food study; the drug can be administered with or without food, so there is no need for fasting," Dr. Itri said.

"The patient takes their pill in front of the doctor, so the doctor knows that the patient has gotten a full dose. There is no compliance question," she further noted. "Then they go home and they come back 3 weeks later."

The starting dose was 27 mg/m² every 3 weeks. For the first half of the trial, the dose was escalated up to 35 mg/m² every 3 weeks if tolerated.

Overall, 20% of women had triple-negative disease, according to results reported in a poster session. More than half each had liver metastases (52%) and lung metastases (57%). Fifty-seven percent had received a taxane as part of their adjuvant therapy.

The median number of cycles of tesetaxel received was 4 (range, 1-17). The overall response rate was 45% (49% in women with estrogen receptor–positive disease and 33% in women with triple-negative disease).

The overall response rate was nearly the same among women who received only the nonescalated dose (44%) and among women who received the escalated dose (47%).

An additional 36% of patients achieved stable disease. Median progression-free survival was 5.8 months for all treated patients and 7.3 months for those with estrogen receptor–positive disease.

"Pretty much, the tolerability profile looks really good," Dr. Itri commented. In particular, none of the patients had hypersensitivity reactions.

By far, the most common grade 3/4 adverse event was neutropenia, seen in 33% of patients overall (26% without dose escalation and 43% with it). However, "none of these patients required a colony-stimulating factor or were febrile. So this now becomes a true outpatient regimen," she said.

The rate of grade 3 peripheral neuropathy was 7% overall (0% without dose escalation and 16% with it), and there was no grade 4 peripheral neuropathy. The rate of grade 2 alopecia was 15% regardless of dose.

Genta sponsored the trial. Dr. Itri disclosed employment and stock ownership in Genta. Dr. Moulder disclosed no relevant conflicts of interest.

CHICAGO – Tesetaxel, an investigational oral taxane, is highly active when used to treat chemotherapy-naive metastatic breast cancer, a phase II trial suggests. And in contrast to the main intravenously administered taxanes, it does not require steroidal premedication and can cause little-to-no peripheral neuropathy.

A total of 46 women were treated with tesetaxel just once every 3 weeks during an office visit in the trial. The overall response rate was 45% – at least a bit higher than the roughly 20%-35% previously seen with the intravenously administered taxanes paclitaxel (Taxol) and docetaxel (Taxotere), according to presenting author Dr. Loretta M. Itri.

"This compares favorably. This is a phase II open-label study. I’m sure the response rate is going to fall a little bit over time, but ... I think we are going to be nothing less than equivalent to the other taxanes," she said in an interview at the annual meeting of the American Society of Clinical Oncology.

A provision for dose escalation from 27 mg/m² to 35 mg/m² was halted halfway through the trial because there was minimal gain in efficacy but substantially more toxicity. "So this [27 mg/m²] is the dose that we will be taking forward in our clinical trials, and we are abandoning escalation," she said. There were no cases of hypersensitivity reaction regardless of dose used; the rate of grade 3 peripheral neuropathy was 16% with dose escalation but 0% without it.

The majority of the patients having progression on treatment had triple-negative disease, Dr. Itri noted. "Now that we know that it’s the triple-negatives who have recently received a taxane who are the ones who don’t respond, we will probably begin excluding that population ... so that we can further enrich [the study population]. We want to give the drug to people whom we can do something good for," she said.

The next step in breast cancer is an ongoing three-arm phase IIb trial comparing tesetaxel given every 3 weeks vs. weekly, and also comparing it with capecitabine (Xeloda), in about 200 patients.

"What’s interesting about the weekly dose is that we have seen in the phase I study no significant neutropenia. So we feel obligated to evaluate the weekly dose, because if we truly had a taxane regimen with no neutropenia, that could be important," said Dr. Itri, an oncologist and chief medical officer of Genta, the company that is developing tesetaxel.

"I will tell you that I have a real bias here ... The weekly dosing is going to really have to be something special for us to abandon the every-3-week dosing, because the convenience and the compliance are so easy," she continued. "These women have a life to live, and the drug was designed to be as user friendly as possible, and I personally don’t like the idea of sending patients home with cytotoxic chemotherapy."

Discussant Dr. Stacy L. Moulder of the University of Texas M.D. Anderson Cancer Center, Houston, noted the advantages of tesetaxel over intravenous taxanes with respect to factors such as oral administration, no need for premedication, and, possibly, reduced toxicity. "But the question that remains is, is this the best microtubule inhibitor?"

She pointed out that a trial of nab-paclitaxel (Abraxane) found approximately double the median duration of progression-free survival seen with tesetaxel in this trial and a fairly similar rate of higher-grade peripheral neuropathy (J. Clin. Oncol. 2009;27:3611-9). "So I think it remains unanswered whether this drug is as good as some of the currently existing novel taxanes," she maintained.

Unlike the intravenous taxanes, tesetaxel is not a substrate for P-glycoprotein (PGP), a transmembrane pump that is likely the main mechanism of taxane resistance, according to Dr. Itri. Thus, it is highly concentrated in cells that overexpress PGP. In preclinical studies, tesetaxel’s cytotoxic activity has been 3-10 times greater than that of the intravenous taxanes in cells not expressing PGP and 10-100 times greater in multidrug-resistant tumor cells overexpressing PGP.

Women were eligible for the trial if they had HER2-negative, chemotherapy-naive metastatic breast cancer. (Those with hormone receptor–positive disease could have received hormonal therapy for their metastases.) Prior adjuvant taxane therapy given more than a year before enrollment was permitted.

The women received single-agent tesetaxel orally once every 3 weeks and without any antiallergy premedication but with an oral antiemetic as a precaution. "We have completed an effect-of-food study; the drug can be administered with or without food, so there is no need for fasting," Dr. Itri said.

"The patient takes their pill in front of the doctor, so the doctor knows that the patient has gotten a full dose. There is no compliance question," she further noted. "Then they go home and they come back 3 weeks later."

The starting dose was 27 mg/m² every 3 weeks. For the first half of the trial, the dose was escalated up to 35 mg/m² every 3 weeks if tolerated.

Overall, 20% of women had triple-negative disease, according to results reported in a poster session. More than half each had liver metastases (52%) and lung metastases (57%). Fifty-seven percent had received a taxane as part of their adjuvant therapy.

The median number of cycles of tesetaxel received was 4 (range, 1-17). The overall response rate was 45% (49% in women with estrogen receptor–positive disease and 33% in women with triple-negative disease).

The overall response rate was nearly the same among women who received only the nonescalated dose (44%) and among women who received the escalated dose (47%).

An additional 36% of patients achieved stable disease. Median progression-free survival was 5.8 months for all treated patients and 7.3 months for those with estrogen receptor–positive disease.

"Pretty much, the tolerability profile looks really good," Dr. Itri commented. In particular, none of the patients had hypersensitivity reactions.

By far, the most common grade 3/4 adverse event was neutropenia, seen in 33% of patients overall (26% without dose escalation and 43% with it). However, "none of these patients required a colony-stimulating factor or were febrile. So this now becomes a true outpatient regimen," she said.

The rate of grade 3 peripheral neuropathy was 7% overall (0% without dose escalation and 16% with it), and there was no grade 4 peripheral neuropathy. The rate of grade 2 alopecia was 15% regardless of dose.

Genta sponsored the trial. Dr. Itri disclosed employment and stock ownership in Genta. Dr. Moulder disclosed no relevant conflicts of interest.

CHICAGO – Tesetaxel, an investigational oral taxane, is highly active when used to treat chemotherapy-naive metastatic breast cancer, a phase II trial suggests. And in contrast to the main intravenously administered taxanes, it does not require steroidal premedication and can cause little-to-no peripheral neuropathy.

A total of 46 women were treated with tesetaxel just once every 3 weeks during an office visit in the trial. The overall response rate was 45% – at least a bit higher than the roughly 20%-35% previously seen with the intravenously administered taxanes paclitaxel (Taxol) and docetaxel (Taxotere), according to presenting author Dr. Loretta M. Itri.

"This compares favorably. This is a phase II open-label study. I’m sure the response rate is going to fall a little bit over time, but ... I think we are going to be nothing less than equivalent to the other taxanes," she said in an interview at the annual meeting of the American Society of Clinical Oncology.

A provision for dose escalation from 27 mg/m² to 35 mg/m² was halted halfway through the trial because there was minimal gain in efficacy but substantially more toxicity. "So this [27 mg/m²] is the dose that we will be taking forward in our clinical trials, and we are abandoning escalation," she said. There were no cases of hypersensitivity reaction regardless of dose used; the rate of grade 3 peripheral neuropathy was 16% with dose escalation but 0% without it.

The majority of the patients having progression on treatment had triple-negative disease, Dr. Itri noted. "Now that we know that it’s the triple-negatives who have recently received a taxane who are the ones who don’t respond, we will probably begin excluding that population ... so that we can further enrich [the study population]. We want to give the drug to people whom we can do something good for," she said.

The next step in breast cancer is an ongoing three-arm phase IIb trial comparing tesetaxel given every 3 weeks vs. weekly, and also comparing it with capecitabine (Xeloda), in about 200 patients.

"What’s interesting about the weekly dose is that we have seen in the phase I study no significant neutropenia. So we feel obligated to evaluate the weekly dose, because if we truly had a taxane regimen with no neutropenia, that could be important," said Dr. Itri, an oncologist and chief medical officer of Genta, the company that is developing tesetaxel.

"I will tell you that I have a real bias here ... The weekly dosing is going to really have to be something special for us to abandon the every-3-week dosing, because the convenience and the compliance are so easy," she continued. "These women have a life to live, and the drug was designed to be as user friendly as possible, and I personally don’t like the idea of sending patients home with cytotoxic chemotherapy."

Discussant Dr. Stacy L. Moulder of the University of Texas M.D. Anderson Cancer Center, Houston, noted the advantages of tesetaxel over intravenous taxanes with respect to factors such as oral administration, no need for premedication, and, possibly, reduced toxicity. "But the question that remains is, is this the best microtubule inhibitor?"

She pointed out that a trial of nab-paclitaxel (Abraxane) found approximately double the median duration of progression-free survival seen with tesetaxel in this trial and a fairly similar rate of higher-grade peripheral neuropathy (J. Clin. Oncol. 2009;27:3611-9). "So I think it remains unanswered whether this drug is as good as some of the currently existing novel taxanes," she maintained.

Unlike the intravenous taxanes, tesetaxel is not a substrate for P-glycoprotein (PGP), a transmembrane pump that is likely the main mechanism of taxane resistance, according to Dr. Itri. Thus, it is highly concentrated in cells that overexpress PGP. In preclinical studies, tesetaxel’s cytotoxic activity has been 3-10 times greater than that of the intravenous taxanes in cells not expressing PGP and 10-100 times greater in multidrug-resistant tumor cells overexpressing PGP.

Women were eligible for the trial if they had HER2-negative, chemotherapy-naive metastatic breast cancer. (Those with hormone receptor–positive disease could have received hormonal therapy for their metastases.) Prior adjuvant taxane therapy given more than a year before enrollment was permitted.

The women received single-agent tesetaxel orally once every 3 weeks and without any antiallergy premedication but with an oral antiemetic as a precaution. "We have completed an effect-of-food study; the drug can be administered with or without food, so there is no need for fasting," Dr. Itri said.

"The patient takes their pill in front of the doctor, so the doctor knows that the patient has gotten a full dose. There is no compliance question," she further noted. "Then they go home and they come back 3 weeks later."

The starting dose was 27 mg/m² every 3 weeks. For the first half of the trial, the dose was escalated up to 35 mg/m² every 3 weeks if tolerated.

Overall, 20% of women had triple-negative disease, according to results reported in a poster session. More than half each had liver metastases (52%) and lung metastases (57%). Fifty-seven percent had received a taxane as part of their adjuvant therapy.

The median number of cycles of tesetaxel received was 4 (range, 1-17). The overall response rate was 45% (49% in women with estrogen receptor–positive disease and 33% in women with triple-negative disease).

The overall response rate was nearly the same among women who received only the nonescalated dose (44%) and among women who received the escalated dose (47%).

An additional 36% of patients achieved stable disease. Median progression-free survival was 5.8 months for all treated patients and 7.3 months for those with estrogen receptor–positive disease.

"Pretty much, the tolerability profile looks really good," Dr. Itri commented. In particular, none of the patients had hypersensitivity reactions.

By far, the most common grade 3/4 adverse event was neutropenia, seen in 33% of patients overall (26% without dose escalation and 43% with it). However, "none of these patients required a colony-stimulating factor or were febrile. So this now becomes a true outpatient regimen," she said.

The rate of grade 3 peripheral neuropathy was 7% overall (0% without dose escalation and 16% with it), and there was no grade 4 peripheral neuropathy. The rate of grade 2 alopecia was 15% regardless of dose.

Genta sponsored the trial. Dr. Itri disclosed employment and stock ownership in Genta. Dr. Moulder disclosed no relevant conflicts of interest.