Geron Corporation’s telomerase inhibitor cancer drug, GRN163L, has demonstrated good pharmacokinetics and tolerability in its ongoing Phase I/II trial involving patients with chronic lymphocytic leukemia (CLL), according to data presented by Alan Colowick, M.D., M.P.H., the company’s president, oncology, at the Pan Pacific Lymphoma Conference in Maui, Hawaii.
A pharmacokinetic analysis of three patients in the highest dose cohort (cohort 4, 160 mg/m2 IV/week) has shown transient peak plasma concentrations of GRN163L of approximately 10 ug/ml. This and other data indicate that the drug continues to exhibit favorable pharmacokinetic properties that are linear with respect to the doses tested so far.
Up to the current dose levels, no significant changes in telomerase activity or telomere length in the bulk circulating CLL cells of treated patients have been observed. These pharmacodynamic results are consistent with expectations because of the relatively short exposure of CLL cells in patients’ blood to concentrations of drug capable of inhibiting telomerase.
With dosing and accrual to cohort 4 continuing, patients treated at the current dose levels have tolerated the drug well, and the maximum tolerated dose has not yet been identified. Grade 1-2 partial thromboplastin time (aPTT) prolongation has been observed, and one patient each has experienced Grade 3 and Grade 4 thrombocytopenia.
One patient in cohort 4 has completed two cycles of treatment, and stable disease has been observed. A second patient has had clinical findings consistent with tumor lysis syndrome, a transient metabolic abnormality resulting from the rapid destruction of malignant cells. This patient experienced a transient reduction in absolute lymphocyte count of 48% that persisted for approximately two weeks. The etiology of this finding is uncertain at this time given the lack of measured telomerase inhibition in this patient.
“We are encouraged by the results,” said Dr. Colowick. “The first and only telomerase inhibitor in clinical trials continues to demonstrate predictable pharmacokinetics over the range investigated and appears to be well tolerated. We will apply what we are learning to the continued dose escalation as we move further into the predicted therapeutic dose cohorts for both the CLL and solid tumor trials. Furthermore, we are adding two additional sites for the CLL trial to accelerate patient enrollment.”
“Based on preclinical data demonstrating the effects of GRN163L on both mature and cancer stem cells in multiple myeloma, Geron will initiate a clinical trial involving multiple myeloma patients,” continued Dr. Colowick. “In addition, the company will begin a fourth trial of GRN163L in combination with carboplatin and paclitaxel in patients with non-small cell lung cancer. The basis for this trial is the result of promising preclinical animal data demonstrating the drug’s activity in this tumor type as well. Geron expects to initiate both trials in the coming months.”
Geron’s ongoing Phase I/II trial is a sequential cohort, dose escalation study to determine the safety and tolerability of GRN163L administered intravenously on a weekly basis to patients with refractory or relapsed CLL.
GRN163L is a short chain oligonucleotide that is unique in its resistance to nuclease digestion in blood and tissues and its very high affinity and specificity for telomerase. The molecule has superior cellular and tissue penetration properties due to its proprietary manufacturing chemistry and its 5’ lipid chain.
GRN163L has been demonstrated to have anti-tumor effects in a wide range of hematological and solid tumor models and appears to be unique in its observed effects on tumor stem cells: the rare, chemotherapy-resistant cancer cells that cause cancer recurrence.