Cixutumumab With Temsirolimus Slows Ewing's Sarcoma

CHICAGO – Two targeted therapies may be better than one for the treatment of refractory Ewing’s sarcoma, according to findings of an early clinical trial reported at the annual meeting of the American Association for Cancer Research.

Combining the investigational agent cixutumumab with temsirolimus (Torisel) resulted in 2 complete responses and 3 partial responses in 17 adolescent and young adult patients with heavily pretreated disease in the phase I clinical trial.

© 2012 AACR/Todd Buchanan

Cixutumumab, a novel monoclonal antibody targeting the insulin-like growth factor 1-receptor (IGF-1R), is under investigation for various cancers. Temsirolimus, a mammalian target of rapamycin (mTOR) inhibitor, is approved for the treatment of advanced renal cell carcinomas.

The two drugs have previously been used as single treatment agents, producing mixed results, according to Dr. Aung Naing of the department of investigational cancer therapeutics at the University of Texas M.D. Anderson Cancer Center in Houston.

Based on data from preclinical studies, "we hypothesized that combining the two could help prevent drug-resistance, which is a common problem in Ewing’s sarcoma," he said in an interview. The two agents target molecular pathways associated with cell proliferation and survival, abnormal blood vessel growth, and resistance to both chemotherapy and radiation therapy, Dr. Naing explained.

To test their hypothesis, the investigators enrolled 20 patients, median age 20 years, with Ewing’s sarcoma (17) or desmoplastic small-round-cell tumors (3) in the trial. The median number of prior therapies per patient was 6. Two patients previously received temsirolimus and six previously received an IGF-1R inhibitor, he said.

All of the patients received 6 mg/kg of intravenous cixutumumab and 25-37.5mg of intravenous temsirolimus weekly for 4-week cycles, with restaging after 8 weeks, Dr. Naing reported.

At a median follow-up of 8.9 months, 7 of the 20 patients (35%) had achieved a complete or partial response or stable disease lasting more than 5 months.

In Ewing’s sarcoma patients specifically, 29% had evidence of tumor regression greater than 20%, Dr. Naing said, noting, "Two patients achieved complete responses, one of which lasted 27 months."

The most frequent, possibly drug-related toxicities included thrombocytopenia (85%), mucositis (80%), hypercholesterolemia (75%), hypertriglyceridemia (70%), and hyperglycemia (65%).

"Most were grade 1-2 [toxicities], but four of the seven best responders developed grade 3 mucositis, myelosuppression, or hyperglycemia, which were managed while maintaining drug dose," Dr. Naing stated.

"Typically, patients who develop these types of grade 3 toxicities would be removed from the study, but we were able to continue with treatment after receiving approval from the sponsor and notification from our institutional review board," he said. Because the toxicities were able to be controlled using supportive measures, "the drug dose did not have to be compromised."

One of the Ewing’s sarcoma patients had achieved a partial response with prior IGF-1R treatment. After initiating the combination therapy, this patient had a mixed response with "remarkable" regression in three lung nodules but progression in a fourth. Morphoproteomic analysis of biopsy samples from this patient demonstrated upregulation of mTOR and ERK/MEK signals, suggesting the possibility that a combination of IGFR/mTOR and MAPK/ERK kinase (MEK) inhibitors might warrant investigation in order to reverse resistance, according to Dr. Naing.

Based on the evidence of activity for the drug combination, the investigators are planning further studies in larger numbers of patients with tumors in the Ewing’s sarcoma family, as well as additional studies into the underlying mechanisms of resistance in individual patients, Dr. Naing said during a press conference.

The results of this study were published simultaneously in Clinical Cancer Research (2012 [doi:10.1158/1078-0432.CCR-12-0061]).

Dr. Naing reported having no relevant financial relationships to disclose.

CHICAGO – Two targeted therapies may be better than one for the treatment of refractory Ewing’s sarcoma, according to findings of an early clinical trial reported at the annual meeting of the American Association for Cancer Research.

Combining the investigational agent cixutumumab with temsirolimus (Torisel) resulted in 2 complete responses and 3 partial responses in 17 adolescent and young adult patients with heavily pretreated disease in the phase I clinical trial.

© 2012 AACR/Todd Buchanan

Cixutumumab, a novel monoclonal antibody targeting the insulin-like growth factor 1-receptor (IGF-1R), is under investigation for various cancers. Temsirolimus, a mammalian target of rapamycin (mTOR) inhibitor, is approved for the treatment of advanced renal cell carcinomas.

The two drugs have previously been used as single treatment agents, producing mixed results, according to Dr. Aung Naing of the department of investigational cancer therapeutics at the University of Texas M.D. Anderson Cancer Center in Houston.

Based on data from preclinical studies, "we hypothesized that combining the two could help prevent drug-resistance, which is a common problem in Ewing’s sarcoma," he said in an interview. The two agents target molecular pathways associated with cell proliferation and survival, abnormal blood vessel growth, and resistance to both chemotherapy and radiation therapy, Dr. Naing explained.

To test their hypothesis, the investigators enrolled 20 patients, median age 20 years, with Ewing’s sarcoma (17) or desmoplastic small-round-cell tumors (3) in the trial. The median number of prior therapies per patient was 6. Two patients previously received temsirolimus and six previously received an IGF-1R inhibitor, he said.

All of the patients received 6 mg/kg of intravenous cixutumumab and 25-37.5mg of intravenous temsirolimus weekly for 4-week cycles, with restaging after 8 weeks, Dr. Naing reported.

At a median follow-up of 8.9 months, 7 of the 20 patients (35%) had achieved a complete or partial response or stable disease lasting more than 5 months.

In Ewing’s sarcoma patients specifically, 29% had evidence of tumor regression greater than 20%, Dr. Naing said, noting, "Two patients achieved complete responses, one of which lasted 27 months."

The most frequent, possibly drug-related toxicities included thrombocytopenia (85%), mucositis (80%), hypercholesterolemia (75%), hypertriglyceridemia (70%), and hyperglycemia (65%).

"Most were grade 1-2 [toxicities], but four of the seven best responders developed grade 3 mucositis, myelosuppression, or hyperglycemia, which were managed while maintaining drug dose," Dr. Naing stated.

"Typically, patients who develop these types of grade 3 toxicities would be removed from the study, but we were able to continue with treatment after receiving approval from the sponsor and notification from our institutional review board," he said. Because the toxicities were able to be controlled using supportive measures, "the drug dose did not have to be compromised."

One of the Ewing’s sarcoma patients had achieved a partial response with prior IGF-1R treatment. After initiating the combination therapy, this patient had a mixed response with "remarkable" regression in three lung nodules but progression in a fourth. Morphoproteomic analysis of biopsy samples from this patient demonstrated upregulation of mTOR and ERK/MEK signals, suggesting the possibility that a combination of IGFR/mTOR and MAPK/ERK kinase (MEK) inhibitors might warrant investigation in order to reverse resistance, according to Dr. Naing.

Based on the evidence of activity for the drug combination, the investigators are planning further studies in larger numbers of patients with tumors in the Ewing’s sarcoma family, as well as additional studies into the underlying mechanisms of resistance in individual patients, Dr. Naing said during a press conference.

The results of this study were published simultaneously in Clinical Cancer Research (2012 [doi:10.1158/1078-0432.CCR-12-0061]).

Dr. Naing reported having no relevant financial relationships to disclose.

CHICAGO – Two targeted therapies may be better than one for the treatment of refractory Ewing’s sarcoma, according to findings of an early clinical trial reported at the annual meeting of the American Association for Cancer Research.

Combining the investigational agent cixutumumab with temsirolimus (Torisel) resulted in 2 complete responses and 3 partial responses in 17 adolescent and young adult patients with heavily pretreated disease in the phase I clinical trial.

© 2012 AACR/Todd Buchanan

Cixutumumab, a novel monoclonal antibody targeting the insulin-like growth factor 1-receptor (IGF-1R), is under investigation for various cancers. Temsirolimus, a mammalian target of rapamycin (mTOR) inhibitor, is approved for the treatment of advanced renal cell carcinomas.

The two drugs have previously been used as single treatment agents, producing mixed results, according to Dr. Aung Naing of the department of investigational cancer therapeutics at the University of Texas M.D. Anderson Cancer Center in Houston.

Based on data from preclinical studies, "we hypothesized that combining the two could help prevent drug-resistance, which is a common problem in Ewing’s sarcoma," he said in an interview. The two agents target molecular pathways associated with cell proliferation and survival, abnormal blood vessel growth, and resistance to both chemotherapy and radiation therapy, Dr. Naing explained.

To test their hypothesis, the investigators enrolled 20 patients, median age 20 years, with Ewing’s sarcoma (17) or desmoplastic small-round-cell tumors (3) in the trial. The median number of prior therapies per patient was 6. Two patients previously received temsirolimus and six previously received an IGF-1R inhibitor, he said.

All of the patients received 6 mg/kg of intravenous cixutumumab and 25-37.5mg of intravenous temsirolimus weekly for 4-week cycles, with restaging after 8 weeks, Dr. Naing reported.

At a median follow-up of 8.9 months, 7 of the 20 patients (35%) had achieved a complete or partial response or stable disease lasting more than 5 months.

In Ewing’s sarcoma patients specifically, 29% had evidence of tumor regression greater than 20%, Dr. Naing said, noting, "Two patients achieved complete responses, one of which lasted 27 months."

The most frequent, possibly drug-related toxicities included thrombocytopenia (85%), mucositis (80%), hypercholesterolemia (75%), hypertriglyceridemia (70%), and hyperglycemia (65%).

"Most were grade 1-2 [toxicities], but four of the seven best responders developed grade 3 mucositis, myelosuppression, or hyperglycemia, which were managed while maintaining drug dose," Dr. Naing stated.

"Typically, patients who develop these types of grade 3 toxicities would be removed from the study, but we were able to continue with treatment after receiving approval from the sponsor and notification from our institutional review board," he said. Because the toxicities were able to be controlled using supportive measures, "the drug dose did not have to be compromised."

One of the Ewing’s sarcoma patients had achieved a partial response with prior IGF-1R treatment. After initiating the combination therapy, this patient had a mixed response with "remarkable" regression in three lung nodules but progression in a fourth. Morphoproteomic analysis of biopsy samples from this patient demonstrated upregulation of mTOR and ERK/MEK signals, suggesting the possibility that a combination of IGFR/mTOR and MAPK/ERK kinase (MEK) inhibitors might warrant investigation in order to reverse resistance, according to Dr. Naing.

Based on the evidence of activity for the drug combination, the investigators are planning further studies in larger numbers of patients with tumors in the Ewing’s sarcoma family, as well as additional studies into the underlying mechanisms of resistance in individual patients, Dr. Naing said during a press conference.

The results of this study were published simultaneously in Clinical Cancer Research (2012 [doi:10.1158/1078-0432.CCR-12-0061]).

Dr. Naing reported having no relevant financial relationships to disclose.