The version I have is from Protocol: 020221, v5.2EU 30APRIL2013
1.1. PROTOCOL TITLE A Phase III Clinical Trial Evaluating DCVax®-L, Autologous Dendritic Cells Pulsed with Tumor Lysate Antigen for the Treatment of Glioblastoma Multiform
2.2. PHASE I/II CLINICAL TRIALS The results of the Phase I/II trials to test the safety and efficacy of DCVax-L are briefly summarized below, and are more fully described in the accompanying Investigator’s Brochure (IB). There is an abundance of cancer literature supporting the safety and potential efficacy of using autologous DC pulsed with autologous tumor lysate antigen, in which 43 trials involving 903 patients are described, with no evidence of serious toxicities or autoimmunity (see IB for a complete listing of references).
The Phase III protocol is predicated on two Phase I/II trials (BB-IND #8434 and #11053) carried out by Dr. Linda Liau and Dr. Robert Prins at the University of California, Los Angeles (UCLA).
Twenty (20) patients with newly diagnosed GBM have been enrolled in 2 Phase I/II trials (data as of June 2011). Patients have been followed for up to 10 years. Sixteen patients have surpassed the historical median time to progression (TTP) of 8.9 months, without evidence of disease progression. Overall, 16 patients have progressed; the four patients with no progression of disease have follow-up times ranging from 43 to 122 months from surgery; these are also the only 4 patients who are still alive. Median progression free survival in these 20 patients is 26.4 months (when McDonald’s criteria are used), and median survival time is 35 months. Historically, at the same institution (UCLA), patients similar to those enrolled in the trial (R.P.A. classes III and IV) have median times to disease progression of 8.9 months (± 7.3 months), and median survival times of 15 months (± 13.9 months). In a multicenter trial, 287 patients treated post surgery with radiotherapy plus concomitant Temodar achieved median progression free survival (PFS) of 6.9 months from surgery (95% confidence interval, 5.8 to 8.2) and median survival of 14.6 months from surgery (95% confidence interval, 13.3 to 16.8; Stupp, 2005). In the Phase II trial, PFS and survival times will be calculated from time of randomization, which is expected to occur approximately three months after initial surgery.
Endpoints - Progression free survival (PFS) and overall survival (OS): Time to objective demonstration of disease progression or death (PFS) or time to death (OS) in patients with either no evidence of disease progression after external beam radiation therapy with concurrent temozolomide chemotherapy, or in patients who show pseudoprogression of disease after external beam radiation therapy with concurrent temozolomide chemotherapy. Patients with pseudoprogression will not be treated with DCVax-L until pseudoprogression (no true disease progression) is confirmed.
3. OVERVIEW OF DCVAX-L PHASE III CLINICAL TRIAL This protocol describes a randomized, placebo-controlled, double blinded, multi-center, multinational
Phase III clinical trial for DCVax-L in patients with newly diagnosed GBM (DCVax-L, when used for primary brain cancer, is sometimes referred to as DCVax-Brain). The primary endpoint for the study is PFS in patients with no progressive disease at baseline. The study is powered such that if the primary endpoint is met, as specified in the statistical considerations section of this protocol, the company intends to request accelerated approval for DCVax-L. In addition, the study is powered to detect meaningful clinical benefit for the secondary endpoint, overall survival (OS), which is also the confirmatory clinical endpoint for the study. Other (tertiary) endpoints include time to progression (TTP), decline in Karnofsky Performance Status (KPS), landmark analyses of survival, and immune responses to DCVax-L, as well as PFS and OS in patients with either no progression or pseudo progression at baseline.
Two weeks after completion of radiation and concurrent chemotherapy treatment, subjects will undergo the Baseline Visit, during which the final tests to determine eligibility are performed. Patients who do not have obvious evidence of progressive disease at the Baseline Visit (as determined by MRI) are enrolled in the main arm of the study (intent to treat), and are randomized to receive DCVax-L in the treatment cohort or autologous MNC in the placebo cohort. Randomization and treatment assignment takes place within 1 week of the Baseline Visit. At the Baseline Visit, patients must be scheduled to return to the clinic 1 week later to receive their first immunization. The study drug, containing approximately 2.5 million DC per immunization (two injections of 1.25 million DC each per immunization, in approximately 150 µl each), is injected i.d. (not subcutaneously) into a clean area of the upper arm, alternating arms between visits. Injection volume is patient specific and the Certificate of Analysis (C of A) should be referenced. Due to the nature of the disease under study, out of window visits are expected for enrolled patients and will not require waivers.
Patients who do not have unequivocal progressive disease but who otherwise have evidence of disease progression (possible pseudoprogression) will initiate adjuvant temozolomide chemotherapy per standard of care, and will be scheduled to return to the clinic at 10 weeks post completion of initial radiation and concurrent chemotherapy treatment to undergo a repeat baseline visit, i.e. Baseline 2 Visit. Patients who do not have progressive disease at the Baseline 2 Visit (as determined by central review of their MRI) are enrolled into the study (intent to treat), and are randomized to receive DCVax-L in the treatment cohort or autologous MNC in the placebo cohort (2:1). Randomization and treatment assignment takes place within 1 week of the Baseline Visit 2. At the Baseline 2 Visit, patients must be scheduled to return to the clinic 1 week later to receive their first immunization. Patients for whom disease progression is confirmed by central review of their Baseline 2 Visit MRI will fail screening and will not be randomized into the study.
Patients who have clear evidence of objective disease progression (measured by MRI, compared with post-surgery MRI and verified by independent review), are not eligible for this study. Patients who do not have progressive disease at baseline are enrolled in the study, and will be randomized to receive DCVax-L or placebo at a 2:1 ratio. All remaining inclusion and exclusion criteria must be met for all patients to be enrolled.
In the event that the scan and or clinical signs cannot unambiguously determine progression or stability (inflammatory artifact, necrosis, other post operative/ radiation changes) then perfusion MRI or other imaging modalities (conforming to local regulation) can be performed at institutional discretion. If tumor status is still equivocal, the patient will be scheduled to return at 10 weeks after the last day of radiation therapy with concurrent temozolomide for a repeat baseline visit: Baseline 2. Baseline 2 Visit is a repeat of the first baseline visit. The patient’s study schedule, timelines and windows, will shift accordingly (by ~8 weeks). A patient who has a Baseline 2 Visit MRI which confirms that the patient does not have disease progression is eligible for enrollment. All decisions regarding tumor progression status are made through independent radiology review.
The following tests and examinations are to be performed at Baseline (Visit 5) and Baseline 2 (Visit 5a): • MRI with and without contrast of the brain to confirm absence of disease progression (verified by independent radiology review) • Physical Examination • Neurological Exam • Vitals • KPS • CBC and differential, Blood chemistry. • Pregnancy test: Serum hCG pregnancy test is performed on female subjects of child bearing potential • Anti-DNA antibodies as a marker of autoimmune disease. Results from this test are not required prior to immunizations • Optional tumor burden tests: Other imaging modalities, conforming to local regulation, may be performed at the investigator’s discretion, or if necessary to determine if recurrence has occurred Eligibility to be enrolled in the study will be determined on the basis of the outcome of these tests, which are to be evaluated within the shortest possible time after the Baseline (or Baseline 2) Visit (target <1 week) to ensure earliest administration of DCVax-L.
And just to clarify decline in KPS score, if a patient clinically deteriorate between between initial screening and baseline, and falls below a 70 KPS score, they are NOT enrolled into the study. If this study used RANO for enrollment, then both psPD and clinical decline (below 70 KPS) would be let in, and clearly this study does not do that.
b) Tests done at the baseline visit complete Screening examinations. The patient must meet all eligibility criteria verified at screening to be enrolled in the study.
Determined at baseline (or baseline2 for pseudoprogression patients) 2 For the purposes of this study, all histologically confirmed, newly diagnosed GBM includes the recognized variants of glioblastoma (giant cell glioblastoma, gliosarcoma, and glioblastoma with oligodendroglial components). • Patients must have a KPS rating of ≥70 at the Baseline Visit (Visit 5) (refer to Appendix D, Performance Status Scales).
APPENDIX D: PERFORMANCE STATUS SCALES KARNOFSKY PERFORMANCE SCALE1 Point Description 100 Normal, no complaints, no evidence of disease 90 Able to carry on normal activity 80 Normal activity with effort, some signs or symptoms of disease 70 Cares for self, unable to carry on normal activity or do active work 60 Requires occasional assistance but is able to care for most of his/her needs 50 Requires considerable assistance and frequent medical care 40 Disabled, requires special care and assistance 30 Severely disabled, hospitalization indicated, death not imminent 20 Very sick, hospitalization necessary, active support treatment necessary 10 Moribund, fatal processes progressing rapidly 0 Dead References: 1. Karnofsky, DA: Meaningful clinical classification of therapeutic responses to anti-cancer drugs. Clin Pharmacol Ther 1961;2:709-712. 2. Stanley, KE: Prognostic factors for survival in patients with inoperable lung cancer. J Natl
Cancer Inst 1980;65:25-32.
RANO criteria follows this, thereby leaving clinical decline of <70KPS in, and also leaves psPD behind. This Phase III does not do that:
"clinical decline alone as well as an increase of contrast enhancement within the radiotherapy field was not considered sufficient for definition of progressive disease within the first 12 weeks after completion of concurrent chemoradiotherapy"
As for crossover, there is a 3 month window, so yes, there will be patients who do not crossover. Events can be backdated to the first sign of disease. Once I find that portion of the protocol that specifically states they do that, I will post it. Clinical decline is not listed as a reason to decline crossover, but I believe they do not give it to patients below KPS 30.
Day 0 is the date of the first immunization and must occur within 3 months of crossover (date of confirmation of disease progression).
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 crossover as 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
As for your question, keep in mind PFS and OS are measured from time of randomization, which is 3 months later.
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