OGX-011 in Combination with Hormone Ablation Therapy in Patients with Localized Prostate Cancer (Clinical Trial OGX-011-01)
For men with localized prostate cancer, hormone ablation therapy with surgery remains the initial standard of care. Hormone ablation causes death of prostate tumor cells.
The purpose of this clinical trial was to:
- determine safety and tolerability and define the recommended Phase 2 dose of OGX-011 when given in combination with hormone ablation therapy;
- determine the concentration and elimination profile of OGX-011 in serum and in the prostate when administered in combination with hormone ablation therapy;
- measure clusterin mRNA and protein levels in the prostate and other tissues and correlate with dose of OGX-011;
measure serum clusterin levels and correlate with dose of OGX-011; and
- attempt to establish possible correlations between plasma and/or prostate concentrations of OGX-011 with patient response or toxicity measures.
In order to determine these objectives, OGX-011 was administered in combination with hormone ablation therapy to patients with localized prostate cancer in advance of a surgical procedure to remove the prostate gland.
There were a total of 25 patients enrolled into treatment groups who received increasing doses of OGX-011 from 40 milligrams (mg) up to 640 mg. There was no dose limiting toxicity observed during OGX-011 dose escalation and adverse events were mild to moderate (grade 1 or 2). In summary, the results of the Phase 1 clinical trial of OGX-011 in combination with hormone ablation therapy were that:
- OGX-011 achieved high drug concentrations in the prostate and lymph nodes through once weekly intravenous administration;
- clusterin mRNA was inhibited in prostate tumor cells by more than 92 percent in patients receiving the highest dose of OGX-011 (640 mg);
- approximately double the amount of tumor cell death occurred in the prostate of patients receiving the highest dose of OGX-011 (640 mg) compared to hormone ablation therapy alone;
- OGX-011 was well-tolerated, with no dose limiting toxicity observed; and
- the recommended Phase 2 dose of OGX-011 was established at 640 mg.
Figure 1: Concentration of OGX-011 in Prostate Tissue
OGX-011 concentration in prostate tissue increased with higher doses, as shown in Figure 1 above. Dose-dependent decreases in clusterin mRNA in prostate tissue were also observed. At the highest dose (640 mg) of OGX-011, clusterin mRNA was decreased by more than 92 percent in prostate tissue when compared to the lowest dose level and other historical controls (patients with no prior hormone ablation therapy and patients with less than two months of hormone ablation therapy), as shown in Figure 2 below. Similarly, clusterin mRNA was decreased by approximately 98 percent in lymph node tissue when compared to the lowest dose level (data not shown).
Figure 2: OGX-011 Inhibits Clusterin mRNA in Prostate Tissue
To determine whether suppression of clusterin levels by OGX-011 treatment could increase tumor cell death in prostate cancer tissue, the percentage of dying tumor cells per high powered field of the microscope were counted as shown in Figure 3 below. At the Phase 2 dose (640 mg) the addition of OGX-011 more than doubled the percentage of dying tumor cells compared to hormone ablation therapy alone.
Figure 3: OGX-011 Increases the Apoptotic Index in Prostatectomy Specimens
These data demonstrate that OGX-011 was able to:
- be delivered to prostate tumors and lymph nodes;
- get inside tumor cells where it is required in order to potentially have a therapeutic effect;
- significantly decrease clusterin production; and
- increase tumor cell death when combined with hormone ablation therapy.
Based on achieving high drug concentration in prostate tissue and over 92 percent inhibition of clusterin mRNA in prostate tumor cells and lymph nodes, and a favorable safety profile, 640 mg was selected as the optimal dose for Phase 2 clinical trials of OGX-011.
Patients in this clinical trial experienced various "adverse events", the majority of which are known to be associated with the other treatments in the protocol (hormone ablation therapy or prostate surgery). An adverse event is any unfavorable and unintended clinical laboratory value or symptom which is encountered during or after the use of an investigational product (i.e. OGX-011). These events may or may not be related to the patient's disease, other therapies administered to the patient or the investigational product.
None of the events that occurred resulted in patients discontinuing OGX-011 and the majority of the adverse events were considered mild. The adverse events thought to be possibly related to OGX-011 occurred mainly within the first week and decreased with continued dosing. These events included mild suppression of white blood cell counts; flu-like symptoms that included fever, fatigue, and rigors; and mild elevations in liver enzyme levels. Most symptoms went away after one to three weeks despite continued administration of OGX-011.
There were no "serious adverse events" reported during this clinical trial. Serious adverse event means any adverse experience that results in any of the following outcomes: death, a life-threatening experience, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a congenital anomaly/birth defect.
OGX-011 in Combination with Docetaxel Chemotherapy in the Treatment of Solid Tumors (Clinical Trial OGX-011-02)
OGX-011 treatment in animal models has been shown to enhance chemosensitivity and to reverse chemotherapy resistance to docetaxel, a chemotherapeutic agent used in a number of cancers including lung, breast, ovarian, bladder, renal cell and hormone refractory prostate cancer. This clinical trial was undertaken to evaluate the safety profile of OGX-011 in combination with docetaxel chemotherapy.
The purpose of this clinical trial was to:
- determine safety and tolerability and define the recommended Phase 2 dose of OGX-011 when given in combination with docetaxel chemotherapy given either weekly or every three weeks;
- determine the concentration of OGX-011 and docetaxel in serum when administered in combination;
- measure evidence of the effect of OGX-011 on serum clusterin levels; and
- document any objective tumor responses.
In order to determine these objectives, OGX-011 was administered in combination with docetaxel chemotherapy to patients with cancers known to over-produce clusterin (prostate, non-small cell lung, breast, ovary, bladder and renal cell).
There were a total of 40 patients enrolled into treatment groups who received increasing doses of OGX-011 from 40 mg up to 640 mg. In addition to OGX-011 treatment, patients also received docetaxel chemotherapy given either as a weekly or every three week schedule as one cycle. The clinical trial was conducted at multiple clinical sites.
Although this was a group of patients with various cancer types, responses and stable disease were documented. OGX-011 treatment resulted in a trend towards dose dependent decreases in serum clusterin levels with the 640 mg dose level having the greatest change from baseline. There was no evidence that administration of OGX-011 affected the metabolism of docetaxel chemotherapy or that docetaxel chemotherapy affected the metabolism of OGX-011.
The recommended OGX-011 dose for treatment in combination with docetaxel chemotherapy was determined as 640 mg, based on acceptable safety results, documented responses/stable disease, and lowering of serum clusterin levels observed from this Phase 1 clinical trial.
Patients in this clinical trial experienced various adverse events, the majority of which are known to be associated with the other treatment in the protocol (docetaxel chemotherapy). Adverse events associated with docetaxel chemotherapy include reduced appetite, nausea, hair loss and decrease in blood counts.
Adverse events were primarily mild to moderate. The incidence of reduced appetite, nausea and hair loss increased as the OGX-011 dose levels increased. The decrease in white blood cell counts was consistent with other trials using docetaxel and did not decrease further with increased doses of OGX-011. Five of the 40 patients experienced dose-limiting toxicity. Four of these events were attributed to the docetaxel chemotherapy and one, fatigue, was attributed to the combination of OGX-011, docetaxel and the disease. Six of the 40 patients experienced a serious adverse event. All of these events were attributed to the docetaxel chemotherapy, except a case of upper gastrointestinal bleeding which was attributed to the combination of OGX-011 and docetaxel chemotherapy.