I should to add that this double-blinded randomized Placebo controlled trial with a crossover will be looking at all study patients WBC effect on OS as an additional covariate in the statistical analysis plan. The poster may have forgotten, but in 2014, they told us they added WBC counts to the statistical analysis, and it will be used to account as possible factors relating to overall survival times. It's a well designed study in my opinion, and that design carries through from newly diagnosed to progression to death, as they look at all factors that might give patients any advantage for both PFS and OS.
"The Company has been blinded at all times, with no access to any data in the Phase III trial, and will remain fully blinded until the trial is completed. The changes relate to the statistical analyses that will be done at the end of the trial, and do not affect the treatment protocol, dosing, randomization of patients or other such aspects. The changes were driven solely by external factors — particularly research reports about a newly discovered variable which has been found to significantly affect GBM patients’ survival times, and which the Company recognized could significantly skew the clinical trial results if the trial’s statistical analyses did not control for it. The Company’s Phase III trial design and statistical analyses already controlled for key variables known at the time when the trial was designed, such as a particular genetic factor (referred to as MGMT methylation), the extent of tumor removal, and others.
The new variable involves the level of certain white blood cells in GBM patients when they finish the 6 weeks of daily radiation to the brain which is part of the current standard of care treatment. Important recent research has found that as many as 40% of GBM patients have such severely depressed white blood cell counts following radiation that their level is comparable to the level at which AIDs patients are put on continuous antibiotic treatments, prophylactically. Further, this research has found that these GBM patients’ white blood cell counts do not recover with the passage of time. See, for example: Grossman et al., 2011: Clin Cancer Res 17(16):5473-80; Ellsworth et al. 2014: Oncoimmunology 3(1):e27357. Epub 2014 Jan 3.
Most importantly, the recent research has identified a major impact on these GBM patients’ Overall Survival (OS): the variable relating to severe depression of white blood cell counts can make a difference of 6 months in OS. As a comparison, the standard of care drug for GBM, Temodar, only makes a difference of 10 weeks in OS. If the statistical analysis of GBM trial results does not take account of such a major variable, the overall trial results could be significantly skewed." --portion of the press release.
Off the old protocol, other prior covariates for PFS:
15.2.3. ANALYTIC METHOD: "The HR will be estimated (Cox proportional hazards regression) and the null hypothesis tested (log-rank test). The Cox model will include treatment group, MGMT methylation status, age, extent of resection, and KPS as covariates. Age, extent of resection (expressed as residual tumor volume after resection), and KPS are considered as factors possibly related to PFS." -- protocol
15.8. ANALYSIS OF COVARIATES The associations of 1) MGMT methylation status, 2) clinical site, 3) RPA classification (a composite score based on age, performance status and extent of resection) and 4) temozolomide usage with PFS and OS will be assessed with Cox proportional hazards regression models. All randomized patients in the main cohort will be included in the analysis. -- protocol
They have a well established placebo controlled trial that clearly takes into account WBC counts effects on survival. And they have well established checks and balances means to determine progression after enrollment for ALL patients.
Progression will be calculated from NADIR tumor burden. NADIR is important as it allow for level of tumor changes allowing for the rock bottom "size" scan; an equal assessment starting point for each patient. And progression as we all know must be determined as unequivocal. Psuedo condition is equivocal. Pathology at the clinical site are the first to review scans and they can do additional imaging to rule out progression (example: perfusion MRI). All imaging assessments to be confirmed by independent pathology, in this trial. See below:
14.2. DEFINITION OF PROGRESSION AFTER ENROLLMENT Progression, calculated from the nadir tumor burden (i.e. post operative, Baseline, or Baseline 2), is defined as one of the following: • In the case of complete resection during primary therapy: a new measurable tumor at the site of the resected tumor, defined as a mass with a longest diameter equal to or greater than 1 cm in at least one dimension. If progression is not defined by these studies, treatment may proceed and determinations made at the next scheduled MRI. • In the case of incomplete resection during primary therapy: a 25% increase or greater in the residual tumor if the recurrent portion of the tumor is at least 1 cm or greater in its longest diameter, measured by MRI and confirmed by scans above as attributable to tumor growth; • If resection is indicated for recurrent disease, while radiographic criteria for progression have not been met: surgical resection, subsequently confirmed as progressive GBM by Pathology at the clinical site and to be confirmed by independent pathology; • Appearance of any new lesion/site at least 1 cm in at least one dimension or greater measured by MRI and confirmed by scans above; • Unequivocal progression of non-measurable disease (either non-enhancing disease seen only on T2/FLAIR images or enhancing disease not meeting size criteria for measurability), such that there is confidence that tumor growth has occurred;4 4 Radbruch et al. 2010: Neuro Oncol. 2011 Dec 6. • Death: all deaths are counted as events for the primary endpoint.
Radiographic evidence of disease progression will be evaluated and corroborated by independent radiology review to determine disease progression for purpose of this trial. MRIs to assess disease progression are done every 2 months.
Unscheduled MRIs or other testing will be recorded in eCRFs. If, during unscheduled procedures, there is evidence of disease progression, it must be confirmed through independent review as described above.
14.3. TIME TO TUMOR PROGRESSION Time to tumor progression is assessed from nadir tumor burden (post operative, Baseline, or Baseline 2) to the date of the first observation of objective disease progression measured by MRI and confirmed if necessary by scans as described above in section 14.2. Patients who have not progressed by the end of the study will continue to be followed for tumor progression or tumor recurrence, for survival (Section 14.5) and for their medical history.
They will be able to DCVax-L credit for OS crossover patients. They will be able to divide suspected immune responders from non-responders, regardless if patients opt in or opt out of crossover. And the protocol adheres to an END OF TREATMENT (EOT) VISIT SCHEDULE AND PROCEDURES (ALL PATIENTS – RANDOMIZED AND CROSSOVER). They know WBC of all patients at the time of elective crossover. All is good. :)
8.4. CROSSOVER (OPEN LABEL) ARM Patients enrolled in the study for whom disease progression is established at any point after randomization (as defined in section 14.2 of this protocol, and verified by independent review) will be offered the opportunity to receive DCVax-L and/or any other established treatment of the physician’s choice. All procedures below should be followed. Patients who do not participate in the crossover option of the study will return for an EOT visit and continue to be followed for survival.
Study Procedures for Crossover (Open Label) Option: Patients who, wish to continue in the study after confirmation of disease progression, will have the option to receive DCVax-L under the crossover/open label option of the study (except in rare cases where they were originally randomized to DCVax-L and have exhausted their supply). Patients enrolled into the crossover arm will be required to follow the same study visit schedule as patients enrolled into the treatment arm of the study (Appendix A1). Patients may be treated with any additional established therapies, and the administration guidelines should be referenced as described below. Labs will be collected prior to the first immunization of a patient following crossoveras specified in 8.4 Labs. A negative urine pregnancy test must be obtained for all female subjects of child bearing potential prior to receiving the immunization.
Immune Monitoring: • Immune monitoring samples will not be drawn for patients enrolled in the crossover study arm
Labs: For all scheduled lab tests during treatment with DCVax-L, central laboratories will be used. Prior to the first immunization of a patient following crossover, the following samples will be collected for the central lab (but results are not required prior to immunization): • CBC and differential • Blood chemistry - Comprehensive metabolic panel, including electrolyte balance, and hepatic and renal functions • Serum hCG for pregnancy • Anti-DNA • Urinalysis • All scheduled and unscheduled MRI and other radiographic images should be sent to central radiology for independent review
Clinical Drug Supply: • Clinical Drug Supply vendor is notified that a patient has confirmed disease progression. Refer to the IXRS manual for further details.
Treatment Schedule after Confirmed Progression and Crossover • Patients will receive up to 10 DCVax-L injections at days 0, 10, 20, and months 2, 4, 8, 12, 18, 24 and 30. Day 0 is the date of the first immunization and must occur within 3 months of crossover (date of confirmation of disease progression). For the immunizations at days 10 and 20, the variance may be ±2 days but the minimum interval between injections must be at least 9 days. For the immunizations at months 2, 4, 8, 12, 18, 24, and 30 the variance can be ±1 week with a minimum interval of 6 weeks between injections. Vitals are recorded every 30 minutes for 2 hours post injection.
Guidelines for Combination Therapy Approaches: If chemotherapies other than temozolomide are combined with DCVax-L following crossover, the following guideline should be used: • A 21 day window surrounding DCVax-L immunizations (10 days before and 10 days after the day of vaccination), during which no chemotherapies (with the exception of temozolomide) should be given, is advised; • Keeping the corticosteroid dose as low as tolerated within the 21 day window around vaccine administration is recommended. Treatment Schedule and Procedures: Follow the schedule of events outlined in Appendix A1, and in Section 8.1 of this protocol as appropriate within the patient’s treatment plan.
Treatment Discontinuation Due to no Study Drug Availability: • If the crossover patient is receiving DCVax-L and no more study drug is available, the patient will discontinue from active treatment, have an End of Treatment (EOT) visit, Section 8.5, and will be followed for survival. Follow-up will be conducted through quarterly phone calls per Sections 11 and 14.5 of the protocol. • An explanation for discontinuing treatment is recorded for each patient on the appropriate eCRF.
8.5. END OF TREATMENT (EOT) VISIT SCHEDULE AND PROCEDURES (ALL PATIENTS – RANDOMIZED AND CROSSOVER): • EOT Visits for all patients who discontinue from the study should occur at least 7 days, but ≤ 30 days, after the last immunization and prior to beginning other treatment. Procedures to be performed during the EOT Visit include: • Physical Exam • Neurological Exam • Vital Signs • KPS • MRI of brain • CBC and Differential • Blood Chemistry - Comprehensive metabolic panel, including electrolyte balance, and hepatic and renal functions • Serum markers of Autoimmune disease (anti-DNA) • Urinalysis • AE Assessment • Concomitant Medication
