Executive Summary

Phase I/II, Arm A: CTO

A recently completed phase I study of CTO in a refractory patient population demonstrated safety and tolerability with no dose limiting toxicities.

Phase I/II Completed Objectives:

  • Determination of Safety and Tolerability of CTO administration to patients with advanced or metastatic solid tumors
  • To determine the Maximum Tolerated Dose (MTD) of CTO

Design:

  • Experimental Arm A (Single agent CTO): Oral admin of CTO daily for 28 day cycles
  • Eight patient cohorts receiving continuous daily oral CTO capsules at doses ranging from 50 mg/m2/day to 555 mg/m2/day

Endpoints:

  • Primary Endpoint

Determine the MTD/RD of single agent CTO in patients with advanced or metastatic solid tumors

  • Secondary Endpoint

Primary tumor response; Tumor genotypes. Pharmacokinetics (Tmax, AUC, clearance, maximum conc.)

Results:

  • CTO is safe and tolerable and has yet to reach MTD at up to 555 mg/m2/day, and therapeutically relevant CAI levels were demonstrated at 219 mg/m2/day dose
  • Nine patients pretreated with different targeted and non-targeted drugs continued dosing beyond 2 cycles and responded to CTO (doses 75mg/m2/day through 427mg/m2/day) and achieved stable disease for different periods (3-14 +months).  The tumors were different types and contained various oncogenic mutations.

2ab62d_1fa1778898af4cfca9609441857b54f8.png_srz_471_453_75_22_0.50_1.20_0.00_png_srzConclusion

CTO alone is safe, tolerated, orally bioavailable and exhibited clinical activity against a broad range of heavily treated refractory tumors with different mutations.

Phase I/II, Arm B: CTO +/- Temodar (NCT01107522)

CTO in combination with Temodar has been administered to 17 patients to date with no grade 4 or 5 adverse events and no dose-limiting events.  MTD has not been determined. As of December 5, 2013, 17 patients with glioblastoma or recurrent malignant gliomas have been treated with Temodar 150 mg/m2 and CTO at doses from 219 through 625 mg/m2/day.  Dose escalation is at CTO 812 mg/m2/day In Arm B of the phase I/II study, four patients treated with CTO + Temodar are continuing treatment with stable disease.

Patient Responses

  • One patient completed 14 cycles of CTO at 285 mg/m2 and maintained partial response since Cycle 2.  This patient with an unmethylated MGMT glioblastoma, which was refractory to Temodar and vandetinib treatment
  • An additional two patients achieved a partial response by the completion of two treatment cycles
  • One patient with unmethylated MGMT negative astrocytoma IV was refractory to Temodar.  The patient achieved durable stable disease for 11 cycles.
  • To date, nine patients completed more than two cycles of therapy with CTO + Temodar.  The median number of treatment weeks in a recent Temodar study was 7 weeks in patients with recurrent or progressive high-grade glioma, and in a recent Avastin study, only 5 of 14 patients with recurrent GBM received more than one treatment cycle

†Temodar alone has no effect in MGMT negative tumors. Therefore, CTO induces sensitivity to and chemosynergy with Temodar Sources: Galldiks N, Berhorn T, Blau T, Dunkl V, Fink GR, Schroeter M. “One week on-one week off”: efficacy and side effects of dose-intensified temozolomide chemotherapy: experiences of a single center. J Neurooncol. 2013 Apr;112(2):209-15. Burkhardt JK, Riina H, Boockvar JA. Intra-Arterial Delivery of Bevacizumab after Blood-Brain Barrier Disruption for the Treatment of Recurrent Glioblastoma: Progression-Free Survival and Overall Survival. World Neurosurg. 2012(1): 130-4; Tactical Therapeutics clinical trial data. January 2014. 2ab62d_421fc3a6129c40428ae8bd7e3dea3cfb.png_srz_766_354_75_22_0.50_1.20_0.00_png_srz

Sources: Tactical Therapeutics clinical trial data. January 2014


 

A partial response has also been demonstrated in MGMT negative patient 004-45.

2ab62d_3e10b946ae1a405c89e8969bea12d21d.png_srz_772_371_75_22_0.50_1.20_0.00_png_srzGBM, MGMT Negative.

 The response in MGMT negative patients, which is a difficult to treat population, indicates an induction of sensitivity to and chemosynergy with Temodar.

Sources: Tactical Therapeutics clinical trial data. January 2014

 GBM, MGMT — ve Avastin Failure

patient4-551
patient4-55updated1

AO, MGMT unknown, Avastin Naive

patient4-561
patient4-56updated1

Results

  • CTO in doses from 219 to 625mg/m2/day in combination with TMZ (150mg/m2) is safe; dose-escalation is at CTO 812 mg/m2/day. MTD has not been determined.
  • Durable Partial Responses (DPR) (6-13+ cycles) have been observed in 4 of 17 refractory patients, some continuing in 14th cycle. 9 of 17 patients received combination treatment beyond 2 cycles.
  • 2 patients with DPR have Negative MGMT status; 1 patient has Positive MGMT status, providing evidence of synergy between CTO and TMZ in chemo-sensitive and chemo-insensitive MG and GBM.
  • These signals of clinical activity in recurrent MG and GBM are encouraging, and a Phase II trial is planned. Other studies started are CTO with TMZ and radiation therapy in newly diagnosed patients, and CTO with bevacizumab, in patients with MG and GBM.