Here is the complete abstracts for the two INFI presentations on IPI-504 at ASCO and my comments:
Abstract 590 summarizes a small open-label p2 in combination with Herceptin in advanced breast cancer. Side effects were acceptable and 1 PR was reported. INFI has disclosed that they will not development IPI-504 further for this indication.
Abstract 7516 summarizes data for a combination of IPI-504 and docetaxel in NSCLC. Side effects were substantial, but PR's were observed in 6 of 23 pts, including 3 of 7 with the subtype of squamous cell carcinoma.
Monday June 6th Poster Presentation Abstract #590
"Efficacy and safety of retaspimycin hydrochloride (IPI-504) in combination with trastuzumab in patients (pts) with pretreated, locally advanced or metastatic HER2-positive breast cancer."
Shanu Modi, MD
Background: Retaspimycin hydrochloride (IPI-504) is a potent, intravenously-administered heat shock protein 90 (Hsp90) chaperone inhibitor. Hsp90 helps maintain the stability of key oncoproteins, including HER2. Preclinical studies have demonstrated the activity of IPI-504 plus trastuzumab in xenograft mouse models using trastuzumab-sensitive and trastuzumab-resistant HER2-positive cell lines.
Methods: In our single-arm, phase 2 study, the overall response rate and tolerability of IPI-504 plus trastuzumab in pts with previously treated, locally advanced or metastatic HER2-positive breast cancer were evaluated. Prior treatment with trastuzumab was required and no limit of previous lines was specified. The trial used a Simon two-stage design; if the DLT rate was "<25% and at least 2 responses were observed, the trial would be expanded.
Results: 26 pts were initially treated with 300 mg/m2 IPI-504 once weekly in combination with 6 mg/kg trastuzumab once every 3 weeks. The median age was 52.5 years (range 33 -72) and the median number of prior regimens received was 6 (range 2-20). Pts received a median of 3 cycles (range 1-12) of IPI-504. No DLTs were reported. The majority of AEs were grade 1 or 2, and the most common treatment-related adverse events were fatigue (46%), nausea (31%), and diarrhea (23%). Related serious adverse events were reported in 2 pts; one pt had Grade 1 diarrhea and Grade 3 hypokalemia, and the other pt had Grade 3 vomiting. Only 1 (4%) Grade 3 transaminase elevation was noted on trial, in a pt with metastatic disease to the liver. Among the 20 pts evaluable for efficacy, 1 partial response was observed (based on central, independent radiology review). Stable disease was observed in 14 pts (70%), including 1 pt (4%) with stable disease for more than 6 months. Conclusions: IPI-504 300 mg/m≤ IV weekly in combination with trastuzumab was well tolerated, without significant hepatic toxicity. Treatment resulted in modest clinical activity in heavily pretreated pts previously exposed to trastuzumab, but did not meet the prespecified efficacy criteria for trial expansion.
Monday June 6th: Poster Presentation Abstract #7516
"Safety and activity of IPI-504 (retaspimycin hydrochloride) and docetaxel in pretreated patients (pts) with metastatic non-small cell lung cancer (NSCLC)."
Gregory J. Riely, MD, PhD
Background: IPI-504, a water-soluble analog of 17-allylamino-17-demethoxygeldanamycin (17-AAG), is an intravenously (IV) administered heat shock protein 90 (Hsp90) inhibitor that causes degradation of a variety of mutated or amplified oncoproteins. The combination of IPI-504 with taxanes has demonstrated additive activity in murine xenograft tumor models.
Methods: An expansion of a Phase Ib trial was undertaken to evaluate IPI-504 in combination with docetaxel in pts with NSCLC and Karnofsky performance status of "e70. Pts had pathologically confirmed metastatic NSCLC; all had received 1 to 2 prior chemotherapy regimens without prior docetaxel. Docetaxel 75 mg/m2 IV was given once every three weeks (wks), while IPI-504 300 mg/m≤ IV was administered once per wk. All pts were evaluated for safety, pharmacokinetics and tumor response (RECIST). Archival tissue samples were required for KRAS genotyping.
Results: The 23 pts included in this analysis received an average of 4 cycles (range 1-13) on study. Median age was 61 years, 13 (57%) were female, and 18 (78%) were current or former smokers, with a median tobacco exposure of 30 pack-years. The majority of adverse events were Grade 1 or 2, and the most common treatment-related adverse events were fatigue (57% total, 4% "eGrade 3), diarrhea (35%, 9%), nausea (30%, 13%), vomiting (30%, 13%), neutropenia (30%, 30%), and anemia (26%, 4%). Docetaxel pharmacokinetics were unaltered by IPI-504 co-administration. 6 of the 23 pts (26%) had a partial response (PR), including 3 of 7 pts with squamous cell carcinoma. Efficacy analysis in overall population and exploratory subgroups is below (Table).
Conclusions: IPI-504 in combination with docetaxel was well tolerated and resulted in clinical activity in pts with pretreated, metastatic NSCLC. A randomized trial is ongoing to evaluate this combination compared to docetaxel plus placebo in this pt population.
Abstract 590 summarizes a small open-label p2 in combination with Herceptin in advanced breast cancer. Side effects were acceptable and 1 PR was reported. INFI has disclosed that they will not development IPI-504 further for this indication.
Abstract 7516 summarizes data for a combination of IPI-504 and docetaxel in NSCLC. Side effects were substantial, but PR's were observed in 6 of 23 pts, including 3 of 7 with the subtype of squamous cell carcinoma.
Monday June 6th Poster Presentation Abstract #590
"Efficacy and safety of retaspimycin hydrochloride (IPI-504) in combination with trastuzumab in patients (pts) with pretreated, locally advanced or metastatic HER2-positive breast cancer."
Shanu Modi, MD
Background: Retaspimycin hydrochloride (IPI-504) is a potent, intravenously-administered heat shock protein 90 (Hsp90) chaperone inhibitor. Hsp90 helps maintain the stability of key oncoproteins, including HER2. Preclinical studies have demonstrated the activity of IPI-504 plus trastuzumab in xenograft mouse models using trastuzumab-sensitive and trastuzumab-resistant HER2-positive cell lines.
Methods: In our single-arm, phase 2 study, the overall response rate and tolerability of IPI-504 plus trastuzumab in pts with previously treated, locally advanced or metastatic HER2-positive breast cancer were evaluated. Prior treatment with trastuzumab was required and no limit of previous lines was specified. The trial used a Simon two-stage design; if the DLT rate was "<25% and at least 2 responses were observed, the trial would be expanded.
Results: 26 pts were initially treated with 300 mg/m2 IPI-504 once weekly in combination with 6 mg/kg trastuzumab once every 3 weeks. The median age was 52.5 years (range 33 -72) and the median number of prior regimens received was 6 (range 2-20). Pts received a median of 3 cycles (range 1-12) of IPI-504. No DLTs were reported. The majority of AEs were grade 1 or 2, and the most common treatment-related adverse events were fatigue (46%), nausea (31%), and diarrhea (23%). Related serious adverse events were reported in 2 pts; one pt had Grade 1 diarrhea and Grade 3 hypokalemia, and the other pt had Grade 3 vomiting. Only 1 (4%) Grade 3 transaminase elevation was noted on trial, in a pt with metastatic disease to the liver. Among the 20 pts evaluable for efficacy, 1 partial response was observed (based on central, independent radiology review). Stable disease was observed in 14 pts (70%), including 1 pt (4%) with stable disease for more than 6 months. Conclusions: IPI-504 300 mg/m≤ IV weekly in combination with trastuzumab was well tolerated, without significant hepatic toxicity. Treatment resulted in modest clinical activity in heavily pretreated pts previously exposed to trastuzumab, but did not meet the prespecified efficacy criteria for trial expansion.
Monday June 6th: Poster Presentation Abstract #7516
"Safety and activity of IPI-504 (retaspimycin hydrochloride) and docetaxel in pretreated patients (pts) with metastatic non-small cell lung cancer (NSCLC)."
Gregory J. Riely, MD, PhD
Background: IPI-504, a water-soluble analog of 17-allylamino-17-demethoxygeldanamycin (17-AAG), is an intravenously (IV) administered heat shock protein 90 (Hsp90) inhibitor that causes degradation of a variety of mutated or amplified oncoproteins. The combination of IPI-504 with taxanes has demonstrated additive activity in murine xenograft tumor models.
Methods: An expansion of a Phase Ib trial was undertaken to evaluate IPI-504 in combination with docetaxel in pts with NSCLC and Karnofsky performance status of "e70. Pts had pathologically confirmed metastatic NSCLC; all had received 1 to 2 prior chemotherapy regimens without prior docetaxel. Docetaxel 75 mg/m2 IV was given once every three weeks (wks), while IPI-504 300 mg/m≤ IV was administered once per wk. All pts were evaluated for safety, pharmacokinetics and tumor response (RECIST). Archival tissue samples were required for KRAS genotyping.
Results: The 23 pts included in this analysis received an average of 4 cycles (range 1-13) on study. Median age was 61 years, 13 (57%) were female, and 18 (78%) were current or former smokers, with a median tobacco exposure of 30 pack-years. The majority of adverse events were Grade 1 or 2, and the most common treatment-related adverse events were fatigue (57% total, 4% "eGrade 3), diarrhea (35%, 9%), nausea (30%, 13%), vomiting (30%, 13%), neutropenia (30%, 30%), and anemia (26%, 4%). Docetaxel pharmacokinetics were unaltered by IPI-504 co-administration. 6 of the 23 pts (26%) had a partial response (PR), including 3 of 7 pts with squamous cell carcinoma. Efficacy analysis in overall population and exploratory subgroups is below (Table).
Conclusions: IPI-504 in combination with docetaxel was well tolerated and resulted in clinical activity in pts with pretreated, metastatic NSCLC. A randomized trial is ongoing to evaluate this combination compared to docetaxel plus placebo in this pt population.
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