A phase II, multi-center, non-randomized, open-label study of TKI258 in patients with relapsed or refractory multiple myeloma, who are with or without t(4;14) translocation

MM is a malignancy of the plasma cell. The malignant plasma cells in bone
marrow produce specific monoclonal immunoglobulin (paraprotein or M-Protein) or
Bence-Jones protein (monoclonal light chains). Proliferation of such abnormal
plasma cells causes bone marrow dysfunction, anemia, and immunosuppression.
Excessive paraprotein may also result in hyperviscocity of serum,
hypercalcemia, and renal impairment.

Despite the array of treatment options, MM remains essentially incurable.
Survival in MM patients may vary from a few months to several years, suggesting
the heterogeneity of the patient population. MM patients, after having received
other approved therapy regimens, have very few options in the relapsed or
refractory setting. In addition, certain subpopulation in MM, e.g. patients
with t(4;14) translocation (occuring in 15% of the MM patients), respond poorly
to standard therapy regimens, and have very poor prognosis. Clearly a need
exists to develop new treatment options, and perhaps to adopt a targeted
approach for sub-populations of MM patients who will benefit from such therapy
in the relapsed or refractory setting.

TKI258 is an inhibitor of Class III/IV/V receptor tyrosine kinases (RTKs).
Activity of RTKs is involved in the growth of different types of tumors as well
as in the initiation, growth, and maintenance of blood vessels supplying the
tumor with blood, oxygen, and nutrients. TKI258 is a multitargeted RTK
inhibitor and may act in this disease state due to its action on more than one
pathway and target.

The t(4;14) translocation that results in translocation of the receptor
tyrosine kinase (RTK) fibroblast growth factor receptor 3 (FGFR3) from
chromosome 4 to the IgH locus. In addition, somatic mutation of FGFR3 occurs
after the translocation event, resulting in constitutive activation of the
receptor in the absence of ligand.

Preclinical data with MM cell lines and xenograft studies with TKI258 support
its investigation in this patient population. These data suggest that TKI258
could also offer therapeutic utility in multiple myeloma patients with or
without the t(4;14) translocation.

As of July 2009, a total of 176 patients were treated with TKI258 in 7 Phase I
single agent clinical studies. These studies demonstrated that 500 mg/day 5
days on/2 days off schedule is well tolerated, and was determined to be the
maximum tolerated dose (MTD).

Dexamethasone is known to increase the response rate and PFS with many of the
approved drugs in MM. An Eastern Cooperative Oncology Group (ECOG) phase III
study compared the high dose dexamethasone with low dose dexamethasone (i.e. 40
mg once every week) in combination regimen with lenalidomide for patients with
MM. The study convincingly showed that the low dose dexamethasone regimen is
actually more effective, and has better safety profile than the high dose
regimens. Thus, as an exploratory objective for this study, patients who have
PD will be allowed to continue on the TKI258 dosing regimen, with the
dexamethasone (40 mg/day) supplementation on days 1, 8, 15, and 22, of each
28-day cycle.

Primary
To assess the extended overall response rates of orally administered TKI258, at
500 mg/day, on a five days on and two days off dosing schedule, in groups of
patients with relapsed or refractory multiple myeloma who are
* with t(4;14) translocation (Group 1).
* without t(4;14) translocation (Group 2).

Secondary
* To assess the safety profile of TKI258 dosing schedule, in the two groups.
* To assess the overall response rates as per IMWG in the two groups.
* To evaluate PFS in the two groups.
* To evaluate plasma exposure of TKI258 in all patients who receive single
agent TKI258.

Exploratory
* To document the response after the addition of dexamethasone to the TKI258
dosing regimen to patients in the two groups when they developed PD on TKI258
monotherapy.
* To evaluate plasma exposure of TKI258 in patients who have dexamethasone
added to the regimen.
* To explore serum DKK1 as a potential prognostic/efficacy marker.
* To explore the serum free light chain as efficacy biomarker.
* To assess the pharmacodynamic (PD) effect of TKI258 on plasma biomarkers
(including but not limited to bFGF, VEGF, PLGF, sVEGFR2
and FGF23) post-treatment.
* To explore the relationship between PK and PD activities of TKI258.
* To understand any possible variability in patients TKI258 disposition through
genotyping TKI258 metabolizing enzymes such as CYP1A1/2.
* To correlate FGFR and VEGF polymorphisms and the patient's response to TKI258.
The following two exploratory objectives are based on the FGFR3 expression or
del(q13) status. Such groups will be analyzed irrespective of the t(4;14)
status of the patient.
* To evaluate extended ORR, ORR, and PFS in patients who are FGFR3 positive,
and those who are FGFR3 negative.
* To evaluate extended ORR, ORR, and PFS in patients who have del(q13), and
those who do not have del(q13).

This is a multi-center, open label, two-stage, phase II trial of TKI258
administered at a dose of 500 mg/day, on a 5 days on/2 days off dosing
schedule, in patients with relapsed or refractory multiple myeloma. Patients
will be stratified into one of the two study groups, as listed below:
Group 1; patients who are t(4;14) positive.
Group 2; patients who are t(4;14) negative.
Patients will be independently recruited on the two groups.
This study will use a two-stage design (Simon, 1989) for both patient groups.
Each group will enroll 20 patients in the first stage and additional 20
patients in the second stage, if the pre-determined response criteria is met
during the first stage. During the first and the second stage additional
patients may be enrolled, to ensure that the required number of patients have
received at least one dose of TKI258.
Patients will receive treatment until disease progression, or unacceptable
toxicities, or until the decision by the physician or the patient to
discontinue.
For patients who are unable to tolerate the protocol-specified dosing schedule
of TKI258, two steps of dose reduction are permitted (from 500mg to 400mg to
300mg).
As an exploratory objective, when a patient reaches progressive disease on the
TKI258 monotherapy regimen, such patients will have an option to continue on
dexamethasone supplemented TKI258 dosing regimen. The Mprotein levels at the
first PD will be considered as the new baseline, and the patients will be
allowed to continue on the dexamethasone supplemented regimen till further
progression, unacceptable toxicity, or patient/physician*s decision to
discontinue.

TKI258: Patients will receive a single daily oral dose of 500 mg TKI258 for 5
consecutive days, followed by a 2 day rest period. This will be repeated for 4
weeks (28 days), which is also defined as one treatment cycle.

Dexamethasone: Low dose dexamethasone (40 mg on day 1, 8, 15, and 22 of each
cycle) will be added to the TKI258 regimen after a patient has developed PD on
single agent TKI258 regimen.

The study will consist of the following parts:
* A baseline or screening period of up to 28 days
* A 28 day treatment cycle that will repeat for as long as there are no severe
side effects or disease progression
* A follow-up period where the patient may be contacted approximately every
month for an update on your general condition, and for evaluating your disease
status

Screening tests include:
* Bone marrow aspirate and biopsy samples will be collected during the
screening visit. For the purposes of this study, further tests will be
performed on the bone marrow aspirate/biopsy samples in a Novartis designated
laboratory to obtain more detail on the status of the multiple myeloma.
* A physical examination and review of how the disease affects the patients
ability to carry out normal activities.
* Measurements of the patients pulse, blood pressure, body temperature, height
and weight.
* Electrocardiogram (ECG), and a multiple gated acquisition (MUGA) scan or an
echocardiogram (ECHO) when a MUGA is not available.
* Measurement of cardiac enzymes
* Blood and urine samples to monitor the safety of treatment with TKI258.
Blood tests include hematology, coagulation, and chemistry.
* Blood and 24-hour urine sample to monitor the multiple myeloma protein levels.
* A pregnancy test will be done in female patients (within 14 days before
treatment start with TKI258). Both male and female patients and their partners
will be asked to use a reliable form of barrier contraception during the entire
study.
* Chest x-ray, CT scanning, and/or other scanning.
* A series of x-rays (sekeletal survey) to evaluate the bones for multiple
myeloma related bone changes
* Relevant medical history/current medical
conditions

The following tests and procedures will be done throughout the study:
* Physical examination: day 1 of cycle 1, day 26 of every cycle, and at the end
of the study.
* Vital signs: days 1 cycle 1, day 26 of every cycle, and at the end of the
study.
* Electrocardiogram (ECGs): days 1 of cycle 1, day 26 of every cycle, and at
the end of the study.
* Multiple gated acquisition (MUGA) or Echocardiogram (ECHO): at baseline, at
the completion of TKI258 therapy cycles, at the end of the optional
dexamethasone supplemented TKI258 therapy, and end of study; cardiac enzymes
will be tested each time MUGA or ECHO is done.
* Blood sampling for Measurement of cardiac enzymes: Blood samples will be
collected at baseline that monitor the health of the heart. If the patient
stays on the treatment for 6 cycles (about 6 months) then a total of 36 ml (~7
teaspoons) of blood will be required for these test.
* Blood sampling for hematology & biochemistry: at baseline, days 1 of cycle 1,
day 26 of each cycle, and at the end of the study; coagulation will be tested
if required during the study and at the end of study. If the patient stays on
the treatment for 6 cycles (about 6 months) then a total of 104 ml (~21
teaspoons) of blood will be required for hematology and biochemistry tests.
* Urinalysis: baseline, day 26 of each cycle, and at the end of the study.
* Blood sampling for pharmacokinetics: days 1 of cycle 1, day 26 of cycle 1 and
2. If all samples are collected, approximately 12 mL (~3 teaspoons) of blood
is needed for each patient. Additional sampling may be collected in situations
such as a decrease in the TKI258 dose, prolonged response, when dexamethasone
is added to the treatment, if a significant adverse event is experienced or a
change in the make up of the study drug.
* Blood sampling for biomarkers: days 1 and 26 of cycle 1, day 26 of each
cycle after cycle 1, and at the end of the study. If all required samples for
biomarker assessments are collected, approximately 95.5 mL (~24 teaspoons) will
be needed for each patient for analysis if the patient stays on the study for 6
cycles (~6 months).
* Bone marrow aspirate/biopsy samples: Bone marrow aspirate samples will be
collected at the baseline, and at the end of cycle 1. Bone marrow biopsy will
be collected at the baseline. Additional bone marrow aspirate samples may be
required during the following treatment cycles to confirm a response to the
TKI258 treatment.
* Disease assessment: disease assessment will be performed every 4 weeks to
review response. Blood samples will be required at the baseline, and at the
end of each cycle. If the patient stays on the treatment for 6 cycles (about 6
months) then a total of 56 ml (~11 teaspoons) of blood will be required. A 24
hour urine sample will be collected at the baseline and at the end of each
cycle for disease assessment purpose.

Risks:
* TKI258 and Dexamethason toxicity
* Reaction on the contrastfluid (used for CT-scans/MRI (optional))
* Possible side effects of the bone marrow biopt (pain, bleeding and infection)
* Possible side effects of bloodsampling (fainting, pain, bleeding, puncture
into the vein,i nfection, and/or bruising)
* Exposure to radiation for x-rays

Benefit:
The group of patients which this study targets has insufficient benefit form
the current treatment options. This new treatment may delay disease
progression.