Phase 1 study of HSP90 inhibitor MPC-3100 in subjects with refractory or recurrent cancer
Link
Background
MPC-3100 is an orally-bioavailable, fully-synthetic inhibitor of the molecular chaperone HSP90. HSP90 is important for post-translational protein folding, stabilization, and function of so-called client proteins, many of which are necessary for growth and survival of cancer cells. In preclinical studies, MPC-3100 has demonstrated client protein modulation and antitumor activity against a broad range of tumor types.
Methods
In this first-in-human, open label, dose escalating, 3+3 design with accelerated titration, multiple-dose study, the safety and tolerability of single agent MPC-3100 were assessed in subjects with recurrent or refractory cancer. Secondary objectives were to characterize the pharmacokinetic parameters (PK) of MPC-3100, assess antitumor activity, and evaluate pharmacodynamic (PD) biomarkers. Subjects received oral MPC-3100 once daily for 21 days followed by 7 days off at doses of 50, 100, 165, 245, or 340 mg/m2 (Cohorts 1-5, respectively) or for 28 days continuously at total daily doses of 480 mg or 640 mg administered as 240 mg or 320 mg Q12H (Cohorts 6 and 7, respectively) per 28-day cycle [This dosing change part of the way through the study was based on preclinical data suggesting eliminating the rest week was advantageous for this drug]. Clinical examinations, blood draws for PK and PD, and tumor assessments were performed at pre-specified times during the study.
Results
MPC-3100 was administered to 26 subjects [13 M, 13 F; median age 63.5 yr, range 45-85 yr; ECOG performance status 0 (n=13), 1 (n=11) and 2 (n=2) at screening; most-represented primary cancer types colon (n=6), prostate (6), and breast (3); median of 4 (range 0 to 16) prior chemotherapies]. The total number of cycles of MPC-3100 administered to all subjects was 44 (median 1, range < 1 to 13). Twenty five subjects experienced at least one potentially drug-related adverse event (AE), the majority of which were Grade 1 and 2, most frequently diarrhea (56%) [This is a class effect for all active HSP90 inhibitors and can be managed propylacticly] , nausea (56%), vomiting (32%), fatigue (32%). Five potentially-related serious AEs (SAEs) were observed in four subjects: abdominal pain, supraventricular tachycardia, respiratory failure, enteritis, and renal failure. The single dose-limiting toxicity (DLT) in this study, Grade 3 supraventricular tachycardia, was observed at the 245 mg/m2 dose level [Cardiac toxicity is always a red flag]. Total daily doses greater than 600 mg were not well tolerated secondary to Grade 1-3 gastrointestinal and Grade 1/2 visual adverse events that resolved following discontinuation of study drug. Hepatotoxicity was not observed in this study. Best clinical response was stable disease in 12/26 (46%) subjects with 6 subjects remaining on study for ≥ 3 cycles [so no partial responses observed, not a surprise since management has been downplaying any efficacy results expectations for this trial]. PK analysis indicated that Cmax and AUC(0-12h) on Day 1 increased in a nearly dose-proportional manner. Terminal plasma half-life ranged from 4.8 to 21.4 hours (mean 11.2 hours). Day 21 exposures were 1.01 to 1.99 times those observed on Day1, indicating a modest degree of drug accumulation. Biomarker analysis demonstrated induction of HSP70 expression at 24 hours post-treatment, and an increase in the degree of HSP70 induction from Day 1 through Day 22, suggesting effective and persistent HSP90 inhibition by MPC-3100 in vivo.
Conclusions
MPC-3100 appears to be safe and tolerable when administered orally at doses below 600 mg per day to subjects with recurrent or refractory cancer. Side-effects were generally manageable or reversible upon discontinuation of MPC-3100. Biomarker modulation indicates appropriate HSP90 inhibition. Nearly half of the subjects attained stable disease. [Interesting that a recommended phase 2 dose was not stated, especially since MYRX is only planning a bioequivalence phase 1 trial with the prodrug form MPC-0767]
Overall, I am not impressed with the potential for this program in the HSP90 inhibitor space. Switching to the prodrug does not appear likely to solve the toxicity problems of MPC-3100. MYRX states they plan a phase 2 in undisclosed cancer indication sometime in 2012 (midyear at earliest I estimate). The fact that this abstract identifies neither a phase 2 dose nor mentions what indication(s) appear promising makes it difficult to predict much about the future direction of the program.
Link
Background
MPC-3100 is an orally-bioavailable, fully-synthetic inhibitor of the molecular chaperone HSP90. HSP90 is important for post-translational protein folding, stabilization, and function of so-called client proteins, many of which are necessary for growth and survival of cancer cells. In preclinical studies, MPC-3100 has demonstrated client protein modulation and antitumor activity against a broad range of tumor types.
Methods
In this first-in-human, open label, dose escalating, 3+3 design with accelerated titration, multiple-dose study, the safety and tolerability of single agent MPC-3100 were assessed in subjects with recurrent or refractory cancer. Secondary objectives were to characterize the pharmacokinetic parameters (PK) of MPC-3100, assess antitumor activity, and evaluate pharmacodynamic (PD) biomarkers. Subjects received oral MPC-3100 once daily for 21 days followed by 7 days off at doses of 50, 100, 165, 245, or 340 mg/m2 (Cohorts 1-5, respectively) or for 28 days continuously at total daily doses of 480 mg or 640 mg administered as 240 mg or 320 mg Q12H (Cohorts 6 and 7, respectively) per 28-day cycle [This dosing change part of the way through the study was based on preclinical data suggesting eliminating the rest week was advantageous for this drug]. Clinical examinations, blood draws for PK and PD, and tumor assessments were performed at pre-specified times during the study.
Results
MPC-3100 was administered to 26 subjects [13 M, 13 F; median age 63.5 yr, range 45-85 yr; ECOG performance status 0 (n=13), 1 (n=11) and 2 (n=2) at screening; most-represented primary cancer types colon (n=6), prostate (6), and breast (3); median of 4 (range 0 to 16) prior chemotherapies]. The total number of cycles of MPC-3100 administered to all subjects was 44 (median 1, range < 1 to 13). Twenty five subjects experienced at least one potentially drug-related adverse event (AE), the majority of which were Grade 1 and 2, most frequently diarrhea (56%) [This is a class effect for all active HSP90 inhibitors and can be managed propylacticly] , nausea (56%), vomiting (32%), fatigue (32%). Five potentially-related serious AEs (SAEs) were observed in four subjects: abdominal pain, supraventricular tachycardia, respiratory failure, enteritis, and renal failure. The single dose-limiting toxicity (DLT) in this study, Grade 3 supraventricular tachycardia, was observed at the 245 mg/m2 dose level [Cardiac toxicity is always a red flag]. Total daily doses greater than 600 mg were not well tolerated secondary to Grade 1-3 gastrointestinal and Grade 1/2 visual adverse events that resolved following discontinuation of study drug. Hepatotoxicity was not observed in this study. Best clinical response was stable disease in 12/26 (46%) subjects with 6 subjects remaining on study for ≥ 3 cycles [so no partial responses observed, not a surprise since management has been downplaying any efficacy results expectations for this trial]. PK analysis indicated that Cmax and AUC(0-12h) on Day 1 increased in a nearly dose-proportional manner. Terminal plasma half-life ranged from 4.8 to 21.4 hours (mean 11.2 hours). Day 21 exposures were 1.01 to 1.99 times those observed on Day1, indicating a modest degree of drug accumulation. Biomarker analysis demonstrated induction of HSP70 expression at 24 hours post-treatment, and an increase in the degree of HSP70 induction from Day 1 through Day 22, suggesting effective and persistent HSP90 inhibition by MPC-3100 in vivo.
Conclusions
MPC-3100 appears to be safe and tolerable when administered orally at doses below 600 mg per day to subjects with recurrent or refractory cancer. Side-effects were generally manageable or reversible upon discontinuation of MPC-3100. Biomarker modulation indicates appropriate HSP90 inhibition. Nearly half of the subjects attained stable disease. [Interesting that a recommended phase 2 dose was not stated, especially since MYRX is only planning a bioequivalence phase 1 trial with the prodrug form MPC-0767]
Overall, I am not impressed with the potential for this program in the HSP90 inhibitor space. Switching to the prodrug does not appear likely to solve the toxicity problems of MPC-3100. MYRX states they plan a phase 2 in undisclosed cancer indication sometime in 2012 (midyear at earliest I estimate). The fact that this abstract identifies neither a phase 2 dose nor mentions what indication(s) appear promising makes it difficult to predict much about the future direction of the program.
Pharmacokinetics, anti-tumor activity and therapeutic index of Nampt inhibitor MPC-8640 in mice
Link
Background:
MPI-0487316 is a potent and orally bioavailable small molecule inhibitor of nicotinamide phosphoribosyltransferase (Nampt), an enzyme which catalyzes the rate-limiting step for synthesis of NAD from nicotinamide. Inhibition of Nampt by MPI-0487316 results in cell death as a consequence of NAD depletion and inhibition of ATP synthesis. We have previously reported that MPI-0487316 can induce regressions in a xenograft model. MPC-8640, a prodrug of MPI-0487316, was developed to increase solubility for improved formulation. Myrexis has recently initiated preclinical development of this prodrug and here we present data on the pharmacokinetic and anti-tumor activity of MPC-8640 in mice.
Methods:
MPI-0487316 concentration in plasma was measured using LC-MS/MS. For xenograft studies, HT1080 human fibrosarcoma cells were implanted subcutaneously into nude mice and mice were administered vehicle or MPC-8640 by oral gavage at the times and doses indicated.
Results:
Oral administration of MPC-8640 to mice resulted in substantial plasma concentrations of the active moiety MPI-0487316 with increasing AUC and Cmax over a wide range of doses. MPC-8640 concentration itself was negligible in plasma when dosed orally at 300 mg/kg. MPC-8640 demonstrated strong activity in the HT1080 human fibrosarcoma xenograft model when dosed qd or bid for one to two weeks. After bid dosing for one week, complete tumor growth inhibition (TGI) was observed at 6 mg/kg and substantial regression at 10 mg/kg. There was no difference between responses after seven or 14 doses bid. For qd dosing, complete tumor growth inhibition required 20 mg/kg MPC-8640 and ≥24 mg/kg for tumor regression. The anti-tumor response seen at the end of seven days of qd dosing was subsequently maintained for at least one week. TGI was observed with three or four doses qd, but with lesser potency than for five or more consecutive qd doses. In studies to determine maximum tolerated dose, 98% of mice survived up to 90 mg/kg MPC-8640 qd for one week, whereas only 60% survived doses >90 mg/kg.
Conclusions:
Oral MPC-8640 is an effective prodrug in mice for systemic delivery of its active moiety Nampt inhibitor MPI-0487316. The lack of significant plasma concentrations of MPC-8640 indicates that the prodrug is effectively converted to active moiety in the gut or immediately after absorption and that anti-tumor activity of MPC-8640 against subcutaneous xenografts is through its active moiety. A one week on / one week off, daily dosing schedule appears optimal, since one week of dosing, either qd or bd, was maximally effective and the anti-tumor response was sustained for at least one week after the end of dosing. Tumor regressions were induced at doses of MPC-8640 well below its maximum tolerated dose, providing promise that MPC-8640 may have anti-tumor activity in the clinic at well-tolerated doses.
Link
Background:
MPI-0487316 is a potent and orally bioavailable small molecule inhibitor of nicotinamide phosphoribosyltransferase (Nampt), an enzyme which catalyzes the rate-limiting step for synthesis of NAD from nicotinamide. Inhibition of Nampt by MPI-0487316 results in cell death as a consequence of NAD depletion and inhibition of ATP synthesis. We have previously reported that MPI-0487316 can induce regressions in a xenograft model. MPC-8640, a prodrug of MPI-0487316, was developed to increase solubility for improved formulation. Myrexis has recently initiated preclinical development of this prodrug and here we present data on the pharmacokinetic and anti-tumor activity of MPC-8640 in mice.
Methods:
MPI-0487316 concentration in plasma was measured using LC-MS/MS. For xenograft studies, HT1080 human fibrosarcoma cells were implanted subcutaneously into nude mice and mice were administered vehicle or MPC-8640 by oral gavage at the times and doses indicated.
Results:
Oral administration of MPC-8640 to mice resulted in substantial plasma concentrations of the active moiety MPI-0487316 with increasing AUC and Cmax over a wide range of doses. MPC-8640 concentration itself was negligible in plasma when dosed orally at 300 mg/kg. MPC-8640 demonstrated strong activity in the HT1080 human fibrosarcoma xenograft model when dosed qd or bid for one to two weeks. After bid dosing for one week, complete tumor growth inhibition (TGI) was observed at 6 mg/kg and substantial regression at 10 mg/kg. There was no difference between responses after seven or 14 doses bid. For qd dosing, complete tumor growth inhibition required 20 mg/kg MPC-8640 and ≥24 mg/kg for tumor regression. The anti-tumor response seen at the end of seven days of qd dosing was subsequently maintained for at least one week. TGI was observed with three or four doses qd, but with lesser potency than for five or more consecutive qd doses. In studies to determine maximum tolerated dose, 98% of mice survived up to 90 mg/kg MPC-8640 qd for one week, whereas only 60% survived doses >90 mg/kg.
Conclusions:
Oral MPC-8640 is an effective prodrug in mice for systemic delivery of its active moiety Nampt inhibitor MPI-0487316. The lack of significant plasma concentrations of MPC-8640 indicates that the prodrug is effectively converted to active moiety in the gut or immediately after absorption and that anti-tumor activity of MPC-8640 against subcutaneous xenografts is through its active moiety. A one week on / one week off, daily dosing schedule appears optimal, since one week of dosing, either qd or bd, was maximally effective and the anti-tumor response was sustained for at least one week after the end of dosing. Tumor regressions were induced at doses of MPC-8640 well below its maximum tolerated dose, providing promise that MPC-8640 may have anti-tumor activity in the clinic at well-tolerated doses.
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