When the study planned to do final analysis based on the trial statistical assumptions and when the injection treatments were scheduled to end are two different things. The study can continue to the end after statistical analysis. However, since we are paying for the study, and they haven't ended it at the designated event count, again, it is my opinion that they will choose to take the study to the very end before doing the statistical analysis. Even the protocol calls for 36 schedule of injections and MRI visits for patients. The consent form details the length of the study. The protocol length of the study matches it. And incidentally the clinical site matches the 10 injection schedule with MRI visit and crossover schedule.
"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)
Northwest Biotherapeutics, Inc.
DCVax®-L, IND #10206
Protocol: 020221, v5.2EU 30APRIL2013 CONFIDENTIAL Page 25 of 57
• Urinalysis
• AE Assessment
• Concomitant Medication" protocol
17.10. INFORMED CONSENT
The PI assumes the responsibility of obtaining written informed consent for each
patient or the patient’s legally authorized representative before any study-specific
procedures are performed.
Patients meeting the criteria set forth in the protocol will be offered the opportunity to
participate in the study. To avoid introduction of bias, the investigator must exercise
no selectivity with regard to offering eligible patients the opportunity to participate in
the study. Patients or parents/legal guardians of all candidate patients will receive a
comprehensive explanation of the proposed treatment, including the nature of the
therapy, alternative therapies available, any known previously experienced adverse
reactions, the investigational status of the study drug, and other factors that are part
of obtaining a proper informed consent. Patients will be given the opportunity to ask
questions concerning the study, and adequate time to consider their decision to or
not to participate.
Informed consent will be documented by the use of a written consent form that
includes all the elements required by FDA regulations and ICH guidelines. The
sponsor or designee will review the informed consent prior to submission to the
IRB/EC. The form is to be signed and dated by the patient or patient's legally
authorized representative and by the person who administers the consent process. A
copy of the signed form will be given to the person who signed it, the original signed
consent form will be filed with the patient’s medical records, and copy maintained
with the patient’s study records. The date and time of time of the informed consent
must be recorded in the source documents.
If an amendment to the protocol changes the patient participation schedule in scope
or activity, or increases the potential risk to the patient, the informed consent
document must be amended. Any amended informed consent must be reviewed by
the sponsor or designee and approved by the IRB/EC prior to use. The revised
informed consent document must be used to obtain re-consent from any patients
currently enrolled in the study if the patient is affected by the amendment, and must
be used to document consent from any new patients enrolled after the approval date
of the amendment.
17.11. INSTITUTIONAL REVIEW BOARD/ETHICS COMMITTEE
The PI will assure that an appropriately constituted IRB/EC that complies with the
requirements of 21 CFR Section 56 or written assurance of compliance with ICH (E6)
guidelines will be responsible for the initial and continuing review and approval of the
clinical study. Before initiation of the study, the PI or designee will forward copies of
the protocol and consent form to be used for the study to the IRB/EC for its review
and approval. A photocopy of the IRB/EC notification of approval must be forwarded
to the Sponsor or its designee before any investigational supplies will be shipped to
the PI.
The PI or designee will also assure that all changes in the research activity and all
unanticipated problems involving risks to human subjects or others will be reported
promptly to the IRB/EC, and that no changes will be made to the protocol without
prior Sponsor and IRB/EC approval, except where necessary to eliminate apparent
immediate hazards to human subjects.
Copies of all study-related correspondence between the investigator and the IRB/EC
must be provided to the Sponsor, or its designee, by the investigator. The PI or
designee must promptly notify the IRB/EC of any SAE occurring at the site and of
any safety reports (e.g., IND Safety Reports) received from the Sponsor, or its
designee, and must copy the Sponsor, or its designee on that correspondence.
The investigator or designee will be responsible for submitting periodic progress
reports to the IRB/EC at intervals appropriate to the degree of patient risk involved in
the study, but not less than once per year and at the completion or termination of the
study.
17.12. PATIENT PRIVACY
The sponsor and the investigator affirm and uphold the principle of the patient's right
to privacy. The Sponsor, it’s designates and the investigator shall comply with
applicable national and local privacy laws.
To verify compliance with this protocol, the Sponsor, or its designee, will require that
the investigator permit the Sponsor, or its designee’s monitor to review the patient's
original medical records. Should access to such medical records require a waiver or
authorization separate from the statement of informed consent, the investigator will
obtain such permission in writing from the patient before the patient is entered into
the study.
18. STOPPING THE STUDY
The sponsor may decide to stop the study at any point, for any reason.
Northwest Biotherapeutics, Inc.
IND #10206
Protocol: 020221, v5.2EU 30APRIL2013 CONFIDENTIAL Appendix A
APPENDIX A: SCHEDULE OF EVENTS
Visit 1 2 3 4 5/5a 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26
Surgery
Post-surgery MRI
Pre-leukapheresis
Leukapheresis
Radiation and
Chemotherapy
Baseline Visit (2) b,n
Enrollment
Immunizations
End of Treatment
Survival Follow-up
1 2 3 4 5 6 7 8 9 10
-1
wk
Time
0d
day
10
day
20
2
Mo
4
Mo
6
Mo
8
Mo
10
Mo
12
Mo
14
Mo
16
Mo
18
Mo
20
Mo
22
Mo
24
Mo
26
Mo
28
Mo
30
Mo
32
Mo
34
Mo
36
Mo
Ongoing
Temozolomide (Stupp Protocol)a
Consent to collect tumor X
Collection of tumor Xm
Consent to Study X
History Xc X
Enrollment & Randomization X
Physical Examq X X X X X X X X X X X X X X X X X X X X X X
Neurological Exam X X X X X X X X X X X X X X X X X X X X X X
Vital Signso X X X X X X X X X X X X X X X X X X X X X X
KPS X X X X X X X X X X X X X X X X X X X X X X
MRI of brain X Xe X X X X X X X X X X X X X X X X X X X
CBC and Differential X X X X X X X X X X X X X X X X X X X X X X X
Blood Chemistryf X X X X X X X X X X X X X X X X X X X X X X X
Urinalysis X X
Pregnancy test X X
anti-DNAg X X X X X X X X X X X X X X X X X X X X
Virology Testingh X
Leukapheresisp X
Blood for Immune Monitoringik X X X X X X X X
Injection of Study Drugj X X X X X X X X X X
AE Assessment X X X X X X X X X X X X X X X X X X X X X X X X
Survivallr X
Footnotes to Schedule of Events A
a) See Appendix B for treatment guidelines
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.
c) Limited history to assess potential study eligibility, including age, absence of prior
malignancies including other brain cancers, no bilateral
disease, no known HIV-1,2 infection, no conflicting prior treatments.
d) Time 0, the day of the first injection, takes place approximately 1 week after the
baseline visit (Visit 5).
e)MRI done 1-3 days after surgery
f) Comprehensive metabolic panel, including electrolyte balance, and hepatic and renal
functions.
g) Anti-DNA antibodies are measured as markers of induced autoimmunity. Results from
this test are not required prior to immunizations.
h) Virology testing is performed prior to leukapheresis.
i) Ten (10) 10mL Green-Top tubes of whole blood plus one Red-Top tube are drawn at Time
0. Subsequent blood draws for immune
monitoring are drawn prior to injection and require ten 10mL Green-Top tubes plus one
Red-Top tube. After the blood draw, the tubes are
shipped to the contract laboratory for development of immune monitoring tests.
j) A sufficient amount of DCVax-L or autologous MNC is shipped to the site for a minimum
of 5 and up to 10 i.d injection visits (2 injections
for each visit). Some patients may not receive 10 immunizations due to insufficient
material, in which case they will receive placebo without
this information being conveyed to the physician or the patient. Due to interference with immune function, it is strongly recommended that adrenal steroids not be used during the 21-day time window that starts 10 days before and ends 10 days after each DCVax-L immunization.
If steroid therapy is clinically indicated, doses should be kept as low as possible (e.g. 2 mg qd).
k) Blood for immune monitoring may only be drawn and shipped M-Th. Immune
monitoring sample shipments will NOT be received on
Saturdays. Please schedule these visits accordingly: Time 0, Day 20, 4 Month, 8 Month,
12 Month, 18 Month, 24 Month, 30 Month. A
window of -2 days is allowable to accommodate Friday shipping restrictions. Samples
should be drawn pre-injection.
l) Survival follow-up will be conducted through quarterly phone calls.
m) Slides for determination of MGMT methylation status should be sent to the central lab.
Refer to the study manual for information on
collecting MGMT methylation status.
n) Patients who may have pseudoprogression will come in for a repeat Baseline Visit, i.e.
Baseline 2. The baseline visit is repeated and the
study schedule is followed without further shift. Patients who have disease progression
determined by the Baseline 2 MRI will screen fail.
Patients who are confirmed to not have disease progression continue on to the first
immunization visit.
Appendix A
o) Vital signs including heat rate, respiration rate, and blood pressure should be collected
pre-injection and every 30 ± 5 minutes for 2 hours
post injection. Pre-injection vitals should be recorded in the eCRF.
p) The standard operating procedures, policies, and guidelines utilized by the apheresis center may supersede the suggested guidelines outlined in this protocol. A patient may have a repeat leukapheresis procedure if the
initial harvest did not generate enough cells to create study drug. Steroids should be stopped or must be tapered to lowest clinically acceptable dose qd approximately 7 days prior to leukapheresis.
q) Physical exam includes height (baseline only) and weight.
r) Includes GBM related health and medical status.
Appendix A1
APPENDIX A1: SCHEDULE OF EVENTS - OPTIONAL CROSSOVER ARM
Footnotes to Schedule of Events- A1 Optional Crossover (Open Label) Arm
a) Physical exam includes weight.
b) Comprehensive metabolic panel, including electrolyte balance, and hepatic and renal functions.
c) Urine Pregnancy Test results will be required prior to the first crossover dose. Serum
pregnancy test will be drawn but results not required prior to
immunization.
d) Anti-DNA antibodies are measured as markers of induced autoimmunity.
e) Results from this test are not required prior to the first immunization.
Crossover Visit C1 C2 C3 C4 C5 C6 C7 C8 C9 C10C11C12C13C14C15C16C17C18C19C20 C21
Immunizations
End of Treatment
Survival Follow-up
1 2 3 4 5 6 7 8 9 10
Time
0
day
10
day
20
2
Mo
4
Mo
6
Mo
8
Mo
10
Mo
12
Mo
14
Mo
16
Mo
18
Mo
20
Mo
22
Mo
24
Mo
26
Mo
28
Mo
30
Mo
32
Mo
34
Mo
36
Mo
Ongoing
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