TLK286 Demonstrates Activity in Platinum and Paclitaxel Resistant and Refractory Ovarian Cancer
Abstract & Commentary
By Robert L. Coleman, MD, Associate Professor, University of Texas; M.D. Anderson Cancer Center, Houston, is Associate Editor for OB/GYN Clinical Alert.
Dr. Coleman is on the speaker’s bureau for GlaxoSmithKline, Bristol-Myers Squibb, and Ortho Biotech.
Synopsis: TLK286 is an active agent in chemotherapy-resistant ovarian cancer. Further studies of TLK286 in platinum and paclitaxel refractory or resistant ovarian cancer are in progress.
Source: Kavanagh JJ, et al. Multi-institutional phase 2 study of TLK286 (TELCYTA, a glutathione S-transferase P1-1 activated glutathione analog prodrug) in patients with platinum and paclitaxel refractory or resistant ovarian cancer. Int J Gynecol Cancer. 2005;15:593-600.
Development and evaluation of novel agents to treat patients with ovarian cancer is a continuous (particularly for recurrent ovarian cancer patients) as well as curative therapy in this setting has yet to be identified. Kavanagh and colleagues studied the clinical activity of a novel glutathione S-transferase (GST) P1-1 analog prodrug, called TLK286, in recurrent ovarian cancer patients. In this open-label, phase II, multi-institutional study, patients with platinum-refractory (defined as progression on front-line platinum-based chemotherapy) and platinum-resistant (defined as progression within 6 months of completion of front-line chemotherapy or progression on a platinum-based re-treatment regimen) ovarian cancer were enrolled. Up to 3 prior regimens were allowed and all platinum-based therapy was considered as one therapy. TLK286 was administered every 3 weeks until progression or toxicity (maximum 6 cycles for responders). In all, 36 patients enrolled. The population had significant drug pre-exposure as the median number of prior regimens was 3. Nearly two-thirds of the study cohort were platinum-refractory and all patients had also failed paclitaxel. The regimen was well tolerated with less than 5% of the cycles requiring dose modifications and/or delays. Only 1 patient experienced hematologic toxicity and only 4 episodes of grade III non-hematologic toxicity was reported. Of the 34 evaluable patients, 5 (15%) achieved a complete or partial response. The median overall survival at 12 months was 60%. Kavanagh et al concluded that the clinical activity of this novel agent was noteworthy, particularly given the nature of the enrolled patients and it compares favorably with other agents used in this setting. A phase III registration trial is currently underway.
Commentary
A continued unmet need in the management of patients with recurrent ovarian cancer is effective therapy in those no longer demonstrating response to platinum and/or a taxane. Although the list of tested chemotherapeutics in this setting is impressive, few agents have even met the bar for second stage accrual under normal phase II design. For instance, in the Gynecologic Oncology Group Protocol series 126—a queue of trials in patients with no more than one prior regimen demonstrating progression on or within 6 months of treatment—fewer than 10 out of the more than 40 agents studied have demonstrated sufficient activity to go onto second stage accrual. It is an arena ripe for clinical investigation, particularly for novel therapeutics.
In the current trial by Kavanagh et al, a rationally designed prodrug, TLK286, was tested in arguably a heavily pretreated and refractory clinical population. The novelty of this agent lies in its activation mechanism. GST P1-1 is an isoform of a cytosolic enzyme that catalyzes the conjugation of electrophilic xenobiotics with glutathione. Its activity is upregulated in many cancers including ovarian cancer, and has been demonstrated to be and adverse prognostic factor. GST P1-1 expression has also been a marker of alkylator drug resistance including the platinates. TLK286 acts as a substrate for this overexpressed enzyme and when metabolized, produces an active agent, which induces the stress response pathway. In this manner, cellular apoptosis occurs in a P53-independent fashion.
Evaluation of TLK286 in vitro and in vivo ovarian cancer models confirmed the exploited pathway is cytotoxic and, thus, should be evaluated clinically in patients. The current phase II trial presented follows Phase I clinical data determining appropriate clinical dosing, both weekly and every 3 weeks—both associated with acceptable and reversible toxicity. While an overall response rate of 15% is not that impressive overall, it is within the context of the patients treated, notably all taxane-refractory and all at least platinum-resistant. It is also notable that the one CR observed occurred in this trial occurred in a platinum/taxane refractory patient with no other chemotherapeutic exposure prior to TLK286. She has maintained her cancer-free status 2.5 years following drug discontinuation.
Ongoing TLK286 single-agent and combination clinical trials will help confirm this drug’s activity in recurrent ovarian cancer. A Phase III clinical trial of combination carboplatin-TLK286 vs pegylated liposomal doxorubicin is underway in patients with platinum-resistant ovarian cancer. Should this benchmark be reached, we will have another agent to add to our armamentarium of chemotherapeutics in the treatment of recurrent ovarian patients.
Development and evaluation of novel agents to treat patients with ovarian cancer is a continuous (particularly for recurrent ovarian cancer patients) as well as curative therapy in this setting has yet to be identified.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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