[runtolive]

Abstract data available
Once every 3 weeks study: 6 of 16 at highest doses with PRs, 5 more have SD, so 11 of 16 responded/responding.

phase 1 dose escalation study.

Once a week study: 7 patients dosed. 3 at 1.2 mg/kg, 3 at 1.6mg/kg, 1 at 2.0mg/kg. MTD not yet established (when the study was submitted of course). 4 patients have PRs (assume that this is ALL of the two higher dose patients (n=4 at two highest doses so far), not confirmed as of the cutoff date, so we'll hear more on them at presentation...NO cardiac-specific toxicity either...

Background: T-DM1 is a first-in-class HER2 antibody-drug conjugate (ADC) in development for HER2-positive BC, and is designed to combine the biological activity of trastuzumab (T) with the targeted delivery of a highly potent antimicrotubule agent (DM1) to HER2-expressing cells. DM1 binds tubulin competitively with vinca alkaloids, 20-100 times more potently than vincristine. T-DM1 binds to HER2 without inducing downregulation with affinity similar to T. T-DM1 has activity in T-sensitive and T-insensitive HER2+ BC xenografts; principal preclinical AEs were reversible transaminase (TA) elevations, reversible platelet decreases, and neuropathy. In a phase I study of T-DM1 given every 3 weeks, the MTD was 3.6 mg/kg, with DLT of gr 4 thrombocytopenia (TCP); tumor responses were seen at doses at or below MTD. The effect of more frequent dosing of T-DM1 on its exposure and safety profile is unknown. Methods: This ongoing phase I study is evaluating the safety and pharmacokinetics (PK) of T-DM1 given IV once weekly to pts with advanced HER2+BC who have progressed on a T- containing regimen. Dose levels for successive cohorts are escalated if DLT is observed in <1/3 of pts within 21 days of first study treatment according to a 3+3 evaluation scheme. Results: Seven pts (median age 53 (range 44-63); all PS 0-1); median number prior metastatic chemo regimens 2 (range 1-4) have received 72 doses of T-DM1 at 3 dose levels (1.2 mg/kg, 3 pts; 1.6 mg/kg, 3 pts; 2.0 mg/kg, 1 pt) on a weekly schedule. Related mild-moderate AEs include fatigue (grade [gr] 1, 3 pts; gr 2, 1 pt), TA elevations gr 2, 1 pt), and headache (gr 2; 1 pt). Related gr >2 AEs have been limited to rapidly reversible TCP (gr 3, 1 pt). No cardiac-specific toxicity has been observed. No DLTs have been observed. Concentration-time profiles appear consistent with predictions based on allometric scaling. Four pts have had partial responses (none confirmed as of the data cutoff date). Conclusions: Related gr >2 AEs have been infrequent and manageable, and objective tumor responses observed, on a weekly schedule of T-DM1. Dose escalation will continue until an MTD is identified. A phase II trial of T-DM1 on a q3-week schedule in advanced HER2+ BC is ongoing.

Background: T-DM1 is designed to combine the biological activity of trastuzumab (T) with the targeted delivery of a highly potent antimicrotubule agent (DM1) to HER2-expressing cells. DM1 binds tubulin competitively with vinca alkaloids, 20-100 times more potently than vincristine. The MCC linker employed in T-DM1 provides a stable bond between T and DM1 that is designed to prolong exposure and reduce the toxicity of T-DM1 while maintaining activity; T-DM1 is the first ADC with an MCC linker in clinical trials.T-DM1 has activity in T-sensitive and T-insensitive HER2+ BC xenografts. Methods: This ongoing phase I study is evaluating the safety and pharmacokinetics (PK) of T- DM1 given IV q3 wks to pts with advanced HER2+ BC who have progressed on a T-containing regimen. Dose levels for successive cohorts were doubled until a related gr 2 AE was observed. Further escalation utilized a 3+3 modified Fibonacci design. Results: Twenty-four pts (median age 50.5 [range 35-70]; all PS 0-1; median number prior metastatic chemo regimens 3 [range 1-7]) have received 156 doses of T- DM1 at 6 dose levels (0.3 mg/kg, 3 pts; 0.6 mg/kg, 1 pt; 1.2 mg/kg, 1 pt; 2.4 mg/kg, 1 pt; 3.6 mg/kg, 15 pts; 4.8 mg/kg, 3 pts). Related grade (gr) 1-2 AEs include TA elevations (gr 1, 5 pts; gr 2, 2 pts), thrombocytopenia (TCP; gr 1, 6 pts; gr 2, 3 pts), fatigue (gr 1, 5 pts; gr 2, 2 pts), anemia (gr 1, 4 pts; gr 2, 3 pts), and neuropathy (gr 1; 2 pts). Related gr 3-4 AEs include rapidly reversible TCP (gr 3, 1 pt; gr 4 [DLT], 2 pts both at 4.8 mg/kg) and neutropenia (gr 3, 1 pt). No cardiac-specific toxicity has been observed. T-DM1 clearance decreased with increasing dose as predicted preclinically. Six of 16 pts at 2.4 or 3.6 mg/kg have had partial responses (5 confirmed); 5 more have stable disease ongoing after 130 to 260 days. Conclusions: The MTD and recommended phase II dose of T-DM1 given IV q3 wks is 3.6 mg/kg. At the MTD, gr >2 AEs related to T-DM1 have been infrequent and manageable. T-DM1 PK is compatible with q3-week dosing. Objective tumor responses have been observed at doses at or below the MTD. A phase II trial in advanced HER2+ BC pts who have progressed on a T-containing regimen is underway; weekly dosing is also being explored.


Background: IMGN242 is a targeted anticancer agent in development for treating CanAg-expressing tumors. In a Phase I clinical study, patients with CanAg-expressing solid tumors were treated with IMGN242 at doses ranging from 18 to 297 mg/m2. A Phase II study was initiated to evaluate IMGN242 for treating CanAg-expressing gastric cancer at the dose of 168 mg/m2. Methods: The pharmacokinetics and safety are being evaluated in on-going Phase I and II studies of IMGN242 given as a single infusion every three weeks. Blood plasma samples were collected throughout the treatment period to determine the pharmacokinetic properties of IMGN242, to evaluate the levels of circulating CanAg and to assess the formation of human anti-IMGN242 antibodies. Assessment of CanAg expression by immunohistochemical staining was performed on tumor biopsies for all patients in the studies. Results: Forty-five patients have been treated with IMGN242 in two clinical trials. Dose limiting toxicities included decreased visual acuity, corneal deposits and keratitis, which appeared to improve in patients where follow-up data is available. A two-phase pharmacokinetic profile was observed for IMGN242 in plasma from patients with low circulating CanAg levels (<1,000 U/mL), with an initial rapid distribution phase that lasted about 48 hours, followed by a slower terminal elimination phase. Eleven patients were noted to have circulating CanAg levels greater than 1,000 U/mL, although there appeared to be no correlation between high plasma CanAg and the pattern of tumor CanAg expression. High plasma CanAg levels appeared to have a marked impact on the pharmacokinetics of IMGN242 with clearance increased 3 to 5-fold in patients with high CanAg (>1,000 U/mL) compared to patients with low levels (<1,000 U/mL). It appeared that patients who developed study drug-related ocular toxicities had low plasma CanAg levels which may correlate with higher IMGN242 exposure in these patients. Conclusions: There appears to be no correlation between the circulating CanAg level and the tumor CanAg antigen expression in patients. Analysis is being performed to further examine the relationship of pharmacokinetics and pharmacodynamics with regards to dose, plasma CanAg level, and tumor CanAg antigen expression.


Background: AVE1642, a humanized mAb, binds the human IGF1R specifically and with high affinity (Kd<1nM). It delays growth of cancer cells in vitro and of human tumors xenografted to nude mice. Materiel and Methods: this study aims to select the dose of AVE1642 to be combined with docetaxel 75 mg/m2 (D). AVE1642 was administered as single agent at cycle(cy)1 and then in combination with D from cy2, q3w. Sequential tumor biopsies were performed in a subset of pts. Main eligibility criteria: > 18y.o; measurable or evaluable advanced ST; PS <2; HbA1c<7.5% or FPG<160mg/dL. PK/PD: blood was collected at d1, d2, d8, d15 and d22 cy1 and cy2 and at d22 of each subsequent cy. Selection of the dose is based on safety (<33% pts with DLT) and on PK, PD parameters. Results: as of 20-Dec-07, 14 pts (4 at 3mg/kg; 4 at 6mg/kg; 4 at 12mg/kg; 2 at 18mg/kg) received 49cy, including 35cy with T. Safety: No DLT/related SAE were reported so far. Gr1/2 related AEs: hyperglycemia(1), hypersensitivity reactions (2), asthenia(2), anemia(1), nail disorder(1), paresthesia(1), pruritus(1). No anti-drug antibodies detected. Activity: 1 pt with breast cancer has had reduction in skin nodules and is on study cy6. In addition, 4 SD confirmed at cy4 are reported (small cell oesophagus, colon, melanoma, epithelioid sarcoma). Preliminary PK/PD data (mean, [CV%], (n)). AVE1642 concentrations increased dose-proportionally. Elimination t½ was UNKNOWN&ap;UNKNOWN 9 days. No PK interaction was observed. At all dose levels, mean IGF1 levels increased up to 6-fold from baseline, plateauing from 14-21d. Conclusion: AVE1642 is well tolerated as single agent and in combination with D. PK/PD data suggest a substantial and maintained biological effect from dose level 3mg/kg.
AVE1642 IGF1
Dose(mg/kg) Cmax(µg/mL) t½(day) CL (L/day) maxEffect(ng/mL) tmax (day)
3 76.4 [12.7] (5) 9.31[17.9] (5) 0.471 [67.9] (5) 558 (3) 63 (3)
6 158 [22.1] (8) 8.60[14] (8) 0.265 [48.4] (8) 589 (3) 63 (3)
12 249 [25.1] (3) 9.01[12.7] (3) 0.281 [23.1] (3) 633 (2) 14 (2)

Background: T-DM1 is a first-in-class HER2 antibody-drug conjugate (ADC) in development for HER2-positive BC, and is designed to combine the biological activity of trastuzumab (T) with the targeted delivery of a highly potent antimicrotubule agent (DM1) to HER2-expressing cells. DM1 binds tubulin competitively with vinca alkaloids, 20-100 times more potently than vincristine. T-DM1 binds to HER2 without inducing downregulation with affinity similar to T. T-DM1 has activity in T-sensitive and T-insensitive HER2+ BC xenografts; principal preclinical AEs were reversible transaminase (TA) elevations, reversible platelet decreases, and neuropathy. In a phase I study of T-DM1 given every 3 weeks, the MTD was 3.6 mg/kg, with DLT of gr 4 thrombocytopenia (TCP); tumor responses were seen at doses at or below MTD. The effect of more frequent dosing of T-DM1 on its exposure and safety profile is unknown. Methods: This ongoing phase I study is evaluating the safety and pharmacokinetics (PK) of T-DM1 given IV once weekly to pts with advanced HER2+BC who have progressed on a T- containing regimen. Dose levels for successive cohorts are escalated if DLT is observed in <1/3 of pts within 21 days of first study treatment according to a 3+3 evaluation scheme. Results: Seven pts (median age 53 (range 44-63); all PS 0-1); median number prior metastatic chemo regimens 2 (range 1-4) have received 72 doses of T-DM1 at 3 dose levels (1.2 mg/kg, 3 pts; 1.6 mg/kg, 3 pts; 2.0 mg/kg, 1 pt) on a weekly schedule. Related mild-moderate AEs include fatigue (grade [gr] 1, 3 pts; gr 2, 1 pt), TA elevations gr 2, 1 pt), and headache (gr 2; 1 pt). Related gr >2 AEs have been limited to rapidly reversible TCP (gr 3, 1 pt). No cardiac-specific toxicity has been observed. No DLTs have been observed. Concentration-time profiles appear consistent with predictions based on allometric scaling. Four pts have had partial responses (none confirmed as of the data cutoff date). Conclusions: Related gr >2 AEs have been infrequent and manageable, and objective tumor responses observed, on a weekly schedule of T-DM1. Dose escalation will continue until an MTD is identified. A phase II trial of T-DM1 on a q3-week schedule in advanced HER2+ BC is ongoing.

Background: T-DM1 is designed to combine the biological activity of trastuzumab (T) with the targeted delivery of a highly potent antimicrotubule agent (DM1) to HER2-expressing cells. DM1 binds tubulin competitively with vinca alkaloids, 20-100 times more potently than vincristine. The MCC linker employed in T-DM1 provides a stable bond between T and DM1 that is designed to prolong exposure and reduce the toxicity of T-DM1 while maintaining activity; T-DM1 is the first ADC with an MCC linker in clinical trials.T-DM1 has activity in T-sensitive and T-insensitive HER2+ BC xenografts. Methods: This ongoing phase I study is evaluating the safety and pharmacokinetics (PK) of T- DM1 given IV q3 wks to pts with advanced HER2+ BC who have progressed on a T-containing regimen. Dose levels for successive cohorts were doubled until a related gr 2 AE was observed. Further escalation utilized a 3+3 modified Fibonacci design. Results: Twenty-four pts (median age 50.5 [range 35-70]; all PS 0-1; median number prior metastatic chemo regimens 3 [range 1-7]) have received 156 doses of T- DM1 at 6 dose levels (0.3 mg/kg, 3 pts; 0.6 mg/kg, 1 pt; 1.2 mg/kg, 1 pt; 2.4 mg/kg, 1 pt; 3.6 mg/kg, 15 pts; 4.8 mg/kg, 3 pts). Related grade (gr) 1-2 AEs include TA elevations (gr 1, 5 pts; gr 2, 2 pts), thrombocytopenia (TCP; gr 1, 6 pts; gr 2, 3 pts), fatigue (gr 1, 5 pts; gr 2, 2 pts), anemia (gr 1, 4 pts; gr 2, 3 pts), and neuropathy (gr 1; 2 pts). Related gr 3-4 AEs include rapidly reversible TCP (gr 3, 1 pt; gr 4 [DLT], 2 pts both at 4.8 mg/kg) and neutropenia (gr 3, 1 pt). No cardiac-specific toxicity has been observed. T-DM1 clearance decreased with increasing dose as predicted preclinically. Six of 16 pts at 2.4 or 3.6 mg/kg have had partial responses (5 confirmed); 5 more have stable disease ongoing after 130 to 260 days. Conclusions: The MTD and recommended phase II dose of T-DM1 given IV q3 wks is 3.6 mg/kg. At the MTD, gr >2 AEs related to T-DM1 have been infrequent and manageable. T-DM1 PK is compatible with q3-week dosing. Objective tumor responses have been observed at doses at or below the MTD. A phase II trial in advanced HER2+ BC pts who have progressed on a T-containing regimen is underway; weekly dosing is also being explored.


Background: IMGN242 is a targeted anticancer agent in development for treating CanAg-expressing tumors. In a Phase I clinical study, patients with CanAg-expressing solid tumors were treated with IMGN242 at doses ranging from 18 to 297 mg/m2. A Phase II study was initiated to evaluate IMGN242 for treating CanAg-expressing gastric cancer at the dose of 168 mg/m2. Methods: The pharmacokinetics and safety are being evaluated in on-going Phase I and II studies of IMGN242 given as a single infusion every three weeks. Blood plasma samples were collected throughout the treatment period to determine the pharmacokinetic properties of IMGN242, to evaluate the levels of circulating CanAg and to assess the formation of human anti-IMGN242 antibodies. Assessment of CanAg expression by immunohistochemical staining was performed on tumor biopsies for all patients in the studies. Results: Forty-five patients have been treated with IMGN242 in two clinical trials. Dose limiting toxicities included decreased visual acuity, corneal deposits and keratitis, which appeared to improve in patients where follow-up data is available. A two-phase pharmacokinetic profile was observed for IMGN242 in plasma from patients with low circulating CanAg levels (<1,000 U/mL), with an initial rapid distribution phase that lasted about 48 hours, followed by a slower terminal elimination phase. Eleven patients were noted to have circulating CanAg levels greater than 1,000 U/mL, although there appeared to be no correlation between high plasma CanAg and the pattern of tumor CanAg expression. High plasma CanAg levels appeared to have a marked impact on the pharmacokinetics of IMGN242 with clearance increased 3 to 5-fold in patients with high CanAg (>1,000 U/mL) compared to patients with low levels (<1,000 U/mL). It appeared that patients who developed study drug-related ocular toxicities had low plasma CanAg levels which may correlate with higher IMGN242 exposure in these patients. Conclusions: There appears to be no correlation between the circulating CanAg level and the tumor CanAg antigen expression in patients. Analysis is being performed to further examine the relationship of pharmacokinetics and pharmacodynamics with regards to dose, plasma CanAg level, and tumor CanAg antigen expression.


Background: AVE1642, a humanized mAb, binds the human IGF1R specifically and with high affinity (Kd<1nM). It delays growth of cancer cells in vitro and of human tumors xenografted to nude mice. Materiel and Methods: this study aims to select the dose of AVE1642 to be combined with docetaxel 75 mg/m2 (D). AVE1642 was administered as single agent at cycle(cy)1 and then in combination with D from cy2, q3w. Sequential tumor biopsies were performed in a subset of pts. Main eligibility criteria: > 18y.o; measurable or evaluable advanced ST; PS <2; HbA1c<7.5% or FPG<160mg/dL. PK/PD: blood was collected at d1, d2, d8, d15 and d22 cy1 and cy2 and at d22 of each subsequent cy. Selection of the dose is based on safety (<33% pts with DLT) and on PK, PD parameters. Results: as of 20-Dec-07, 14 pts (4 at 3mg/kg; 4 at 6mg/kg; 4 at 12mg/kg; 2 at 18mg/kg) received 49cy, including 35cy with T. Safety: No DLT/related SAE were reported so far. Gr1/2 related AEs: hyperglycemia(1), hypersensitivity reactions (2), asthenia(2), anemia(1), nail disorder(1), paresthesia(1), pruritus(1). No anti-drug antibodies detected. Activity: 1 pt with breast cancer has had reduction in skin nodules and is on study cy6. In addition, 4 SD confirmed at cy4 are reported (small cell oesophagus, colon, melanoma, epithelioid sarcoma). Preliminary PK/PD data (mean, [CV%], (n)). AVE1642 concentrations increased dose-proportionally. Elimination t½ was UNKNOWN&ap;UNKNOWN 9 days. No PK interaction was observed. At all dose levels, mean IGF1 levels increased up to 6-fold from baseline, plateauing from 14-21d. Conclusion: AVE1642 is well tolerated as single agent and in combination with D. PK/PD data suggest a substantial and maintained biological effect from dose level 3mg/kg.
AVE1642 IGF1
Dose(mg/kg) Cmax(µg/mL) t½(day) CL (L/day) maxEffect(ng/mL) tmax (day)
3 76.4 [12.7] (5) 9.31[17.9] (5) 0.471 [67.9] (5) 558 (3) 63 (3)
6 158 [22.1] (8) 8.60[14] (8) 0.265 [48.4] (8) 589 (3) 63 (3)
12 249 [25.1] (3) 9.01[12.7] (3) 0.281 [23.1] (3) 633 (2) 14 (2)