Principle Investigator at University Health Network, Princess Margaret Cancer Centre, Dr. Girish Kulkarni MD, Surgeon-Scientist affiliated with the Department of Surgery, Faculty of Medicine at the University of Toronto discusses the successful completion of the first human clinical study for Theralase’s Anti-Cancer Study Drug, TLD-1433.
Phase Ib NMIBC Clinical Study
The Phase Ib NMIBC clinical study (“Study I”) is entitled,
“A Phase Ib Trial of Intravesical Photodynamic Therapy in Patients with Non-Muscle Invasive Bladder Cancer at High Risk of Progression Who are Refractory to Therapy with Bacillus Calmette-Guérin (“BCG”) and Who are Medically Unfit for or Refuse a Cystectomy”.
The Study’s purpose was to evaluate TLD-1433, Theralase’s lead PDC for the primary endpoint of safety and tolerability, a secondary endpoint of pharmacokinetics (movement and exit of drug within tissue) and an exploratory endpoint of efficacy, primarily at 90 days and secondarily at 180 days post treatment.
Theralase has completed a Phase Ib NMIBC clinical study (“Study”), with 6 patients treated at University Health Network (“UHN”) (Toronto, Ontario, Canada).
- Three patients to have the Maximum Recommended Starting Dose (“MRSD”) of the Study Drug (TLD-1433) instilled intravesically into their bladder, light activated by fibre optics placed inside the bladder connected to the Study Device (TLC-3200 Medical Laser System) at a specific target energy density.
- If the MRSD of the Study Drug is proven safe after independent review by the Data Safety Monitoring Board (“DSMB”), then an additional three patients would be treated at the Therapeutic Dose (“Therapeutic Dose”) (2 times the MRSD) of the Study Drug (TLD-1433) instilled intravesically into their bladder, light activated by fibre optics placed inside the bladder connected to the Study Device (TLC-3200 Medical Laser System) at a specific target energy density.
Study Outcome Endpoints:
Evaluate safety and tolerability. Primary endpoint of safety achieved after 6 patients treated in the Study experienced only grade 1 and grade 2 Adverse Events (“AEs”) (e.g.: bladder spasms, constipation, urge incontinence, fatigue, urinary frequency, hematuria, penile discomfort, urinary urgency, pain and other), where 95% of these AEs resolved within 180 days. For the 5% of AEs not completely resolved, all were considered pre-existing conditions in the opinion of the Principal Investigator (“PI”) and hence none were deemed related to the Study.
Evaluate the pharmacokinetics. Secondary endpoint achieved at the Therapeutic Dose: 89.0% of the Study Drug was excreted from urine within 24 hours and 99.9% was excreted within 72 hours post Study Treatment. In plasma, 68% was removed within 24 hours and 90% removed within 72 hours post Study Treatment. See Figure 1.
Evaluate efficacy. CR rates were demonstrated in 67% of patients (2 out of 3 patients) treated at the Therapeutic Dose of the Study Drug at the 90 day assessment. This CR rate of 67% (2 out of 3 patients) continued up to 450 days post initial treatment (540 days post Study Treatment).
This latest data validates the strong efficacy signal that the Company has received after only a single ACT treatment in the completed Study I, representing a 67% CR in the Therapeutic Dose group.
The Medical and Scientific Advisory Board (“MSAB”) recommended that the clinical data collected from six patients in Study I were sufficient to support the conclusion that Study I had successfully achieved Study I’s primary and secondary endpoints and had adequately addressed the Study’s scientific, technical and clinical questions, as per the approved Study design and clinical protocol. The MSAB recommendation to the Company was to terminate Study I based on the six patients treated and suggested that the Company immediately pursue a pivotal Phase II NMIBC clinical study approval with Health Canada and the Food and Drug Administration (“FDA”) to commence Study II, with a the primary objective of efficacy.
FDA guidelines (February 2018) for BCG-Unresponsive Non Muscle Invasive Bladder Cancer states that:
“In BCG-unresponsive NMIBC, a single-arm clinical trial with Complete Response rate and duration of response as the primary endpoint can provide primary evidence of effectiveness to support a marketing application”
For NMIBC, a CR is defined by the FDA as the definitive endpoint for single-arm intravesical studies of patients who present with BCG-Unresponsive Carcinoma In-Situ (“CIS”) disease, with or without resected papillary tumours, at any point in time and to demonstrate duration of CR at 360 days post initial CR.
Theralase’s ACT involves the intravesical instillation of a water-based solution of the lead PDC, TLD-1433, via a catheter inserted through the urethra into the patient’s bladder, allowing the PDC to be preferentially absorbed by NMIBC tumours.
The bladder is then drained of the solution, flushed with sterile water to remove non-absorbed TLD-1433 and refilled with sterile water via a cystoscope.
The Study Device (TLC-3200), is a fiber optic assembly, containing a Laser Emitter used to emit laser light and a Laser Detector used to measure the intensity of laser light delivered. When the Study Device is inserted through the cystoscope and once positioned, the laser light is emitted to activate the Study Drug absorbed in the cancer cells to produce singlet oxygen and ROS to induce the cancer cell into natural death, known as apoptosis, through oxidative stress.
Pivotal Phase II NMIBC Clinical Study
Since April 2019, Theralase has commenced Phase II NMIBC Clinical Study.
The pivotal Phase II NMIBC Clinical Study, entitled:
“A Phase II Clinical Study of Intravesical Photo Dynamic Therapy in Patients with BCG-Unresponsive Non-Muscle Invasive Bladder Cancer or Patients Who are Intolerant to BCG Therapy” (“Study II”)
Study II will utilize the Therapeutic Dose (0.70 mg/cm2) of TLD-1433 and will focus on the enrollment and treatment of approximately 100 to 125 BCG-Unresponsive NMIBC patients presenting with CIS in approximately 20 clinical sites located in Canada and the United States, with a primary endpoint of efficacy, a secondary endpoint of duration of efficacy and a tertiary endpoint of safety.
Phase II Progress
To date two of four clinical study sites in Canada have enrolled and treated 12 patients; University Health Network (“UHN”) (Toronto, Ontario) and McGill University Health Centre (“MUHC”) (Montreal, Quebec).
Additional clinical study sites include London Health Sciences Centre (“LHSC”) and the Nova Scotia Health Authority (“NSHA”).
|Clinical Study Sites||Principle Investigator|
|University Health Network, Princess Margaret Cancer Centre||Dr. Girish Kulkarni, MD, PhD, FRCSC|
|McGill University Health Centre||Dr. Wassim Kassouf, MD, CM, FRCSC|
|London Health Sciences Centre||Dr. Joseph Chin, MD, FRSC|
|Nova Scotia Health Authority||Dr. Ricardo Rendon, MD, FRCSC|
Study Interim Results:
Primary Endpoint of Efficacy Achieved. Efficacy of 25.0% (3 out of 12 patients) CR at 90 days post initial Study II Treatment. Efficacy of 33.3% (5 out of 15 patients) CR at 90 days post initial Study II Treatment for all 15 patients treated at the Therapeutic Dose in the Phase Ib and II clinical study, combined.
Secondary Endpoint of Duration of CR Pending – Two out of three patients treated in the Study at the Therapeutic Dose in the Phase Ib study demonstrated a duration of CR of 450 days post-initial CR. Duration of CR for patients in Study II is currently pending.
Tertiary Endpoint of Safety Achieved - All AEs observed have been Grade 1 (mild) or Grade 2 (moderate) (e.g.: bladder spasms, constipation, urge incontinence, fatigue, urinary frequency, hematuria, penile discomfort, urinary urgency, pain, urinary tract infections and other) due to the Study Treatment with 46% fully resolving within 90 days. There was one Grade 3 (severe) AE recorded for one patient, who developed symptoms of acute microbial infection. The patient was prescribed antibiotics, which mitigated the bacterial load within a few days. The Grade 3 AE was considered not Study Treatment related.
The Phase II NMIBC clinical study at an interim analysis has met all primary, secondary and tertiary objectives at 90 days post initial Study II Treatment demonstrating a strong efficacy, duration and safety profile. Theralase will continue to enroll and treat patients to increase patient number and provide additional clinical data on all endpoints.
In addition to CRs, there are two patients who are demonstrating Partial Responses (“PRs”) (negative cystoscopy and positive urine cytology). If Upper Tract Urothelial Cell Carcinoma (“UTUCC”) or urothelial carcinoma of the prostatic urethra is ruled out, these patients have the potential to become CRs, in accordance with the FDA’s guidance to industry.
Final clinical data from the completed Phase Ib clinical study and interim clinical data from the Phase II clinical study for patients with BCG-Unresponsive, NMIBC CIS strongly support Theralase’s® contention that the Study Treatment offers a new and advanced treatment option for these patients, who have exhausted all other available treatment options, with 1/3 of patients treated at the Therapeutic Dose, now being diagnosed as cancer free.
The Study Treatment represents a unique approach, using a targeted and patient specific treatment methodology.
If Study II demonstrates strong endpoint results, similar to those attained in the Study, with a high safety profile, then the evidence could support an application for commercialization with the potential of being eligible for Fast Track Approval (“FTA”), Breakthrough Therapy Designation (“BTD”) and/or Accelerated Approval (“AA”), pending Study II results.
IMPORTANT INFORMATION FOR PATIENTS
If you are a patient interested in participating in the Phase II NMIBC clinical study (“Study II”), please feel free to contact Theralase® or the nearest participating clinical study site for more information.
If enrolled in Study II, there is a no charge for participation. for patients who qualify; however, your urologist will need to contact the principal investigator to provide confidential information about your NMIBC to ensure you meet the clinical study guidelines.
For patients or practitioners wishing to learn more about Study II, please visit ClinicalTrials.gov and search for "Theralase" or by the National Clinical Trial Number: NCT03945162.
Medical and Scientific Advisory Board
Dr. Michael Jewett
MD, University Health Network
Chairman of the Medical and Scientific Advisory Board (“MSAB”) for NMIBC, Professor of Surgery (Urology) at University of Toronto, Surgical Oncology at Princess Margaret Cancer Centre, University Health Network (“UHN”), Clinical practice is in urologic oncology with research interests in testicular cancer and superficial bladder cancer
Ashish M. Kamat
MD, MBBS, FACS, Professor of Urology, MD Anderson
Internationally recognized expert in urologic oncology and an authority in the management of urologic cancers with expertise in bladder cancer, organ sparing and minimally invasive techniques. Maintains an active research portfolio with focus on efforts to develop novel therapies and identify predictors of response to therapy. Initiated, led and active in several large studies including multinational trials in bladder cancer, findings published in high impact journals.
Dr. Michael A. O’Donnell
MD, Professor of Urology, University of Iowa
Long history of focusing on bladder immunology and bladder cancer immunotherapy, particularly the anticancer mechanism of Bacillus Calmette-Guerin (“BCG”) and its enhancement with combination therapies. Recently headed a national trial of bladder cancer treatment utilizing BCG plus interferon (a natural protein which induces health cells to combat disease) comprised of over 1,000 patients and holds several US patents for his work.
PhD, Scientific Principal Investigator, University Health Network
Professor in the Department of Medical Biophysics at the University of Toronto and Senior Scientist at the Ontario Cancer Institute, Princess Margaret Cancer Center, UHN. Research is focused on photo dynamic therapy, optical diagnostics, destruction of cancer and bacteria by light activated PDC’s and the use of light as a microscopic tool for biomedical research.
Brian C. Wilson
PhD, University Health Network
Dr. Wilson is a Senior Scientist and Head of the Applied Biophotonics group at Princess Margaret Cancer Centre, University Health Network and Professor in the Department of Medical Biophysics at the University of Toronto. Research focus of the Applied Biophotonics group is the development and application of new therapeutic and diagnostic techniques based on the use of lasers and other optical technologies.
Expertise in biomedical
and clinical research
Our Medical and Scientific Advisory Board ("MSAB") is comprised of international key opinion leaders and esteemed scientists with broad expertise in biomedical and clinical research, drug discovery and development, as well as, medical device engineering and manufacturing. The MSAB plays an active role in Theralase® pipeline's development with evaluation of in-licensing and partnership opportunities.
The MSAB members meet regularly with the Theralase® team to maximize the chances of success of each of TLT and PDT operational divisions platform technology pipelines. Together, members of the Medical and Scientific Advisory Board provide critical evaluation and guidance of our proposed and current programmes to ensure that our research is focused and cutting-edge.
of scientific capabilities
Theralase® has a unique combination of scientific capabilities in medical devises and small light-activated molecules discovery, design and development. This puts us in a strong position to develop the targeted innovative, science based, medical technology platforms required to meet patient needs.
To increase the value of our pipeline we are not only applying the best science and technology, but also employing a comprehensive strategy to safeguard our intellectual property through patent protection.
PhD, Scientific Principal Investigator
Professor in the Department of Medical Biophysics at the University of Toronto, Senior Scientist Ontario Cancer Institute, Princess Margaret Cancer Center
Research Scientist, DVM, MS, PhD
Cancer Therapy – Immunotherapy
Research Scientist, PhD
Immunolgy – Cardiovascular Biology
Research Scientist, PhD
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