Phase I-II Everolimus and Sorafenib in Recurrent High-Grade Gliomas

Background

- Although malignant gliomas display genetic heterogeneity, several key proliferation and
survival signaling pathways have been identified.

- Recent work has focused on targeting these tumor specific pathways in hopes of improving
treatment efficacy and minimizing treatment toxicity. Because molecularly targeted
agents have been mostly ineffective when used alone, combination therapy that inhibits
multiple pathways is an appealing strategy.

- Sorafenib is an oral multi-kinase inhibitor with effects on tumor proliferation and
tumor angiogenesis. Although most GBMs lack RAF mutations, targeting the RAF/MEK/ERK
pathway may be beneficial as this pathway may be activated by other genetic alterations
upstream from RAF.

- The mammalian target of rapamycin (mTOR) protein is a downstream component of the
PI3K/Akt pathway. Everolimus (everolimus; Novartis) is a novel oral derivative of
rapamycin.

- Combining everolimus and sorafenib allows targeting of both the PI3K pathway and the
RAF-MAPK pathway and in addition targets VEGF and PDGF, other active targets in
malignant glioma.

Objectives

Phase 1

-To determine the maximum tolerated dose and safety of everolimus in combination with

sorafenib for patients with recurrent malignant gliomas.

Phase 2

- 6 month progression free survival rate for glioblastoma patients with no prior
bevacizumab exposure treated with everolimus and sorafenib at the maximum tolerated dose
as determined in the phase I study.

- 3 month progression free survival rate for glioblastoma patients with prior bevacizumab
exposure treated with everolimus and sorafenib at the maximum tolerated dose as
determined in the phase I study.

- 6 month progression free survival rate for AG patients with no prior bevacizumab
exposure treated with everolimus and sorafenib at the maximum tolerated dose as
determined in the phase I study.

Eligibility

- Patients with histologically proven recurrent intracranial malignant glioma will be
eligible for the phase I/II component of this protocol.

- Patients must be >= 18 years old with a Karnofsky performance status of greater than or
equal to 60

- No more than 2 prior chemotherapies and 1 relapse. Prior bevacizumab therapy is allowed.

Design

- This is a phase 1 /2 study of everolimus and sorafenib in patients with recurrent
highgrade gliomas.

- Phase 1: Patients will be treated with daily everolimus (days 1-28) in combination with
sorafenib.

- Phase 2: Patients will be treated with the combination of sorafenib and everolimus.
Sorafenib will be taken daily for 7 days on, then 7 days off. Everolimus will be taken
daily.

- There is not a defined set maximum number of cycles that a patient may have. Patients
may continue with protocol therapy until criteria for Off Treatment is met. Patients
will then be followed every 3 months for survival status.

- There will be an accrual of approximately 3-6 eligible patients per cohort to the Phase
I component of the study. Patients removed at any time for toxicity are evaluable. Phase
I patients removed from study treatment within 28 days for reasons other than toxicity
may be replaced.

- There will be a total accrual of approximately 82 eligible patients to the Phase II
study (34 recurrent GBM with no prior exposure to bevacizumab, 16 recurrent Anaplastic
Glioma with no prior exposure to bevacizumab, and 32 glioblastoma with prior exposure to
bevacizumab).

- INCLUSION CRITERIA:

General Inclusion Criteria

1. Patients with histologically proven recurrent intracranial malignant glioma will be
eligible for the phase I/II component of this protocol. Malignant glioma includes
glioblastoma (GBM), Gliosarcoma (GS), anaplastic astrocytoma (AA), anaplastic
oligodendroglioma (AO), anaplastic mixed oligoastrocytoma (AMO), or malignant
astrocytoma NOS (not otherwise specified). Patients will be eligible if the original
histology was low-grade glioma and a subsequent histological diagnosis of a malignant
glioma is made.

2. All patients must sign an informed consent indicating that they are aware of the
investigational nature of this study. Patients must have signed an authorization for
the release of their protected health information at all sites except the NIH.

3. Patients must be greater than or equal to 18 years old.

4. Patients must have a Karnofsky performance status of greater than or equal to 60.

5. No more than 2 prior chemotherapies and 1 relapse. Prior bevacizumab therapy is
allowed.

-Patients must have recovered from the toxic effects of prior therapy: >3 weeks for
biologic therapies or non-cytotoxic therapies, >4 weeks for cytotoxic therapies, and
>6 weeks for nitrosoureas. Any questions related to the definition of non- cytotoxic
agents should be directed to the Study Chair.

NOTE: 13 cis-retinoic acid (Accutane) as biologic therapy has a washout period of 14
days.

6. Patients must have adequate bone marrow function (WBC >= 3.0 x 10^9/L, ANC >= 1.5 X
10^9/L, platelet count of >=100 x 10^9/L, and hemoglobin >= 10 gm/dL), adequate liver
function (SGOT and bilirubin < 2 times ULN), and adequate renal function (creatinine <
1.7mg/dL or creatinine clearance greater than or equal to 60 cc/min) before starting
therapy. These tests must be performed within 14 days prior to registration.
Eligibility level for hemoglobin may be reached by transfusion.

7. Patients must have shown unequivocal radiographic evidence for tumor progression by
MRI or CT scan. A scan should be performed within 14 days prior to registration and on
a steroid dose that has been stable or decreasing for at least 5 days. If the steroid
dose is increased between the date of imaging and registration a new baseline MRI/CT
is required. The same type of scan, i.e., MRI or CT must be used throughout the period
of protocol treatment for tumor measurement. Measurable disease is NOT required.

Note: MRI is the preferable imaging method; CT scan may be used in cases where an MRI
cannot be obtained.

8. Patients having undergone recent resection of recurrent or progressive tumor will be
eligible as long as all of the following conditions apply:

- They have recovered from the effects of surgery and be > 3 weeks from surgery.

- Residual disease following resection of recurrent malignant glioma is not
mandated for eligibility into the study. To best assess the extent of residual
disease post-operatively, a CT/ MRI should be done no later than 96 hours in the
immediate post-operative period or at least 4 weeks post-operatively, within 14
days prior to registration. If the 96-hour scan is more than 14 days before
registration, the scan needs to be repeated. If the steroid dose is increased
between the date of imaging and registration, a new baseline MRI/CT is required
on a stable steroid dosage for at least 5 days.

9. Patients must have failed prior radiation therapy and must have an interval of greater
than or equal to 12 weeks from the completion of radiation therapy to registration;
except if patients underwent surgery within 12 weeks and pathology is consistent with
recurrent tumor.

10. Patients with prior therapy that included interstitial brachytherapy or stereotactic
radiosurgery must have confirmation of true progressive disease rather than radiation
necrosis based upon either PET or Thallium scanning, MR spectroscopy or
surgical/pathological documentation of disease.

11. Women of childbearing potential must have a negative B-HCG pregnancy test documented
within 7 days prior to taking the first dose of study medications.

12. Patients receiving anti-coagulation treatment with an agent such as warfarin or
heparin may be allowed to participate. For patients on warfarin, the INR should be
measured prior to initiation of sorafenib and monitored at least weekly, or as defined
by the local standard of care, until INR is stable.

Phase I Inclusion Criteria:

The following modifications to the general eligibility criteria apply to Phase I patients
only.

-Patients may have had treatment for any number of prior relapses. Relapse is defined as
progression following initial therapy (i.e. surgery and radiation+/- chemo if that was used
as initial therapy).

Phase II Inclusion Criteria:

Phase II patients must meet the following Eligibility Criteria in addition to the General
Criteria described above.

- Patients may have had treatment for no more than 1 prior relapse (i.e. failed 2 lines
of treatment-initial therapy and therapy for first relapse) at 2nd relapse, treatment
per BTTC09-01 is an option. Relapse is defined as progression following initial
therapy (i.e. radiation+/- chemo if that was used as initial therapy). The intent
therefore is that patients had no more than 2 prior therapies (initial and treatment
for 1 relapse). If the patient had a surgical resection for relapsed disease and no
anti-cancer therapy was instituted for up to 12 weeks, and the patient undergoes
another surgical resection, this is considered as 1 relapse. For patients who had
prior therapy for a low-grade glioma, the surgical diagnosis of a high-grade glioma
will be considered the first relapse.

- Patients must not have received prior therapy with sorafenib, everolimus, or related
drugs such as tyrosine kinase inhibitors, VEGF inhibitors (except bevacizumab), or
mTOR inhibitors.

EXCLUSION CRITERIA:

General Exclusion Criteria

1. Patients has any significant medical illnesses that in the investigator s opinion
cannot be adequately controlled with appropriate therapy or would compromise the
patient s ability to tolerate this therapy

2. Patients with a history of any other cancer (except non-melanoma skin cancer or
carcinoma in-situ of the cervix), unless in complete remission and off of all therapy
for that disease for a minimum of 3 years are ineligible.

3. Patients has an active infection or serious intercurrent medical illness.

4. Patients has any disease that will obscure toxicity or dangerously alter drug
metabolism.

5. Patients must not be on enzyme inducing anti-convulsants. If patients were previously
on EIAEDs and these have been discontinued, patients must have been off the agent for
at least 2 weeks prior to first study drug administration. For patients who need to
start an AED or the AED needs to be changed, it is strongly recommended that all
efforts should be made to use a non-EIAED.

6. Patients who have any severe and/or uncontrolled medical conditions or other
conditions that could affect their participation in the study such as: Symptomatic
congestive heart failure of New York heart Association Class III or IV unstable angina
pectoris, symptomatic congestive heart failure, myocardial infarction within 6 months
of start of study drug or any other clinically significant cardiac disease severely
impaired lung function as defined as spirometry and DLCO that is 50% of the normal
predicted value and/or 02 saturation that is 88% or less at rest on room air
uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN, active (acute or
chronic) or uncontrolled severe infections, liver disease such as cirrhosis, chronic
active hepatitis or chronic persistent hepatitis.

7. Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy.

8. Uncontrolled hypertension defined as systolic blood pressure > 140 mmHg or diastolic
pressure > 90 mmHg, despite optimal medical management.

9. Known human immunodeficiency virus (HIV) infection or chronic or acute Hepatitis B or
C. Note: Patients who have a history of HBV and HCB infection are eligible, however,
they must receive prophylactic antiviral therapy for 1-2 weeks prior to receiving
study drug

10. Thrombolic or embolic events (except DVT or pulmonary embolus) such as a
Cerebrovascular accident including transient ischemic attacks within the past 6
months.

11. Pulmonary hemorrhage/bleeding event greater than or equal to CTCAE Grade 2 within 4
weeks of first dose of study drug.

12. Any other hemorrhage/bleeding event greater than or equal to CTCAE Grade 3 within 4
weeks of first dose of study drug.

13. Serious non-healing wound, non-healing ulcer, or bone fracture.

14. Evidence or history of bleeding diathesis or coagulopathy

15. Major surgery, open biopsy or significant traumatic injury within 4 weeks of first
study drug.

16. Use of St. John s Wort, orrifampin (rifampicin), or other strong CYP34A inducers.
Dexamethasone is okay as long as the dose is 16 mg /day or less.

Note: Patients who are on the above referenced medications may be considered eligible
with a washout period of 14 days. Contact the coordinating center to discuss patients
with the above aforementioned agents before patient registration.

17. Known or suspected allergy to sorafenib, everolimus, or any agent given in the course
of this trial.

18. Any condition that impairs patient s ability to swallow whole pills.

19. Any malabsorption problem.

20. Other malignancies within the past 3 years except for adequately treated carcinoma of
the cervix or basal or squamous cell carcinomas of the skin.

21. Female patients who are pregnant or breast feeding, or adults of reproductive
potential who are not using effective birth control methods. Barrier contraceptives
must be used throughout the trial by both sexes. Hormonal contraceptives are not
acceptable as a sole method of contraception. (Women of childbearing potential must
have a negative urine or serum pregnancy test within 7 days prior to administration of
everolimus and sorafenib).

22. Patients who have received prior treatment with an mTOR inhibitor (sirolimus,
temsirolimus, everolimus).

23. Patients with a known hypersensitivity to everolimus or other rapamycins (sirolimus,
temsirolimus) or to its excipients.

24. History of noncompliance to medical regimens.

25. Patients unwilling to or unable to comply with the protocol.

26. Patients on total daily dose of dexamethasone greater than 16 mg.