BGB-290-104: A Phase 1b/2 study to assess the safety, tolerability and efficacy of BGB-290 in combination with radiation therapy and/or temozolomide in subjects with first-line or recurrent/refractory glioblastoma

Glioblastomas (GB), the most aggressive subtype of gliomas, harbor a range of
oncogenic mutations. These mutations are associated with resistance to both
chemotherapy and radiation therapy (RT). A substantial number of these genetic
alterations affect key players in deoxyribonucleic acid (DNA) repair pathways.

• Methylation of the O6-methylguanine-DNA methyltransferase (MGMT) gene
promoter and Mismatch Repair (MMR) gene mutations:
• Downregulation of the p53 signaling pathway: Around 70% of GB patients were
reported to have somatic mutations affecting the p53 pathway
• Downregulation of the retinoblastoma (RB) signaling pathway: RB1 and its
paralogs p107 and p130 play a central role in DNA double strand break (DSB)
repair by non-homologous end joining
• Upregulation of the epidermal growth factor receptor
(EGFR)/Ras/phosphatidylinositol-3-OH kinase (PI3K) signaling pathway through
PTEN alterations:

The high frequency of genetic alterations in GB affecting DNA repair pathways
suggests that DNA-damaging agents or agents interfering with DNA repair may be
able to provide clinical benefit for GB patients. This hypothesis is supported
by the current standard of care for GB patients but has not been adequately
explored for other classes of drugs, such as inhibitors of poly(ADP-ribose)
polymerase (PARP).

Because of the infiltrative nature of GB, surgery alone is never curative.
Therefore, the majority of patients are subsequently treated with RT, with or
without chemotherapy. In 2005, Stupp and colleagues published a landmark study
demonstrating a 2.5-month overall survival (OS) benefit with the addition of
the alkylating agent temozolomide (TMZ) to surgery and RT . The results of this
large trial established the role of TMZ, along with maximal safe resection and
RT, for the treatment of newly diagnosed GB patients <65 years old. Preliminary
evidence that inactivation of the MGMT protein conferred sensitivity to TMZ and
TMZ*s efficacy in recurrent glioma served as supporting data for this large,
randomized, Phase 3 trial. Subset analyses confirmed
improved survival and sensitivity to TMZ for tumors deficient in MGMT (defined
by MGMT promoter methylation) compared to those with adequate MGMT expression
(defined by an unmethylated MGMT promoter).

Ionizing radiation used in the clinical treatment of GB generates mostly
single-strand breaks (SSBs) and to a minor extent DSBs. Single-strand breaks
are repaired through the BER pathway, operating via either the short patch or
the long patch repair sub-pathways, which differ in the size of the repair
patch and the enzymes involved. A PARP-1 role in the short patch is well
established, but its contribution in the long patch is still unclear. In
non-replicating cells, PARP inhibition only delays the repair of SSBs induced
by radiation with a minimal impact on cell survival. On the contrary, PARP
inhibition markedly enhances radiosensitivity of proliferating cells since
unrepaired SSBs
collide with the DNA replication machinery, generating DSBs. Thus, PARP
inhibitors have the potential to increase the anti-tumor effect of RT by
preventing DNA damage repair and increasing cytotoxic DNA damage.

PARP-1 and PARP-2 have a key role in the base excision repair (BER) of
N-methylpurines (N7-methylguanine and N3-methyladenine) that are generated by
TMZ. In the presence of a functional BER system these damaged bases are
promptly repaired and limit TMZ cytotoxicity. The first step of the BER process
is the excision of the modified base by N-methylpurine glycosylase (MPG)
resulting in an apurinic/apyrimidinic (AP) site that is subsequently cleaved by
apurinic/apyrimidinic endonuclease. The resultant DNA nicks are finally
repaired by the coordinate intervention of PARP-1, DNA polymerase, XRCC1 and
ligase III. Inhibition of PARP activity hampers PARylation of PARP-1 and
PARP-2, interrupting the completion of the repair process mediated by BER .
Combining PARP inhibition with DNA-damaging TMZ leads to increased DNA damage
that results in apoptosis and/or growth arrest. Repeated treatments with
TMZ and PARP inhibitors also downregulate transcription and delay recovery of
BER
components in tumor cells . This mechanism might further enhance the cytotoxic
effects of TMZ combined with a PARP inhibitor.

In glioma cells, pharmacological modulation of PARP activity increased growth
inhibition by TMZ in both p53-wild-type and p53-mutant glioblastoma cells and
markedly lowered the TMZ IC50 to levels below the concentration of TMZ that can
be detected in the plasma or brain of treated patients. The most pronounced
effect was observed in tumor cells resistant to TMZ due to high MGMT levels or
to MMR deficiency. In fact, in short-term primary cultures of glioma cells
derived from surgical specimens, the enhancement of chemosensitivity to TMZ
induced by a PARP inhibitor was especially evident in MGMT-proficient cells.
Moreover, in an MMR-deficient glioma cell line, in which an MGMT inhibitor
would have been ineffective, the combination of TMZ with the PARP inhibitor
reverted resistance to the methylating compound . These data suggest that GB
patients who derive less benefit from current standard of care because of lack
of MGMT promoter methylation may benefit from a combination regimen that
includes a PARP inhibitor.

Non clinical data suggests BGB-290 is a highly potent and selective inhibitor
of PARP1 and PARP2 that sets itself apart from other PARP inhibitors by
combining potent DNA-trapping activity with good brain penetrance.

Aside from surgical resection and RT as main standards of care. Glioblastomas
have a high prevalence of alterations affecting DNA repair. There is strong
scientific rationale that PARP inhibitors may provide anti-tumor activity in
GB, in particular when combined with standard-of-care DNA-damaging RT and/or
TMZ. These novel combinations may furthermore be able to overcome resistance in
GBs with unmethylated MGMT promoter.

Primary objectives:
Phase 1b:
Arm A (BGB-290 + radiation therapy [RT]): Subjects with first-line glioblastoma
(GB) with unmethylated MGMT promoter (*unmethylated GB*)
• To assess safety and tolerability of BGB-290 combined with RT
• To identify dose-limiting toxicity (DLT) and determine the maximum tolerated
dose (MTD) or maximum administered dose (MAD) for BGB-290 combined with RT
• To select the recommended Phase 2 schedule for full-dose BGB 290 combined
with RT Arm B (BGB-290 + RT + temozolomide [TMZ]): Subjects with first-line
unmethylated GB
• To assess safety and tolerability of BGB-290 combined with RT and TMZ
• To identify DLTs and determine the MTD or MAD for TMZ combined with RT and
the MTD/MAD for BGB-290 of Arm A
• To select the RP2D for TMZ combined with RT and the MTD/MAD for BGB-290 of
Arm A Arm C (BGB-290 + TMZ): Subjects with recurrent/refractory GB
• To assess safety and tolerability of BGB-290 combined with TMZ
• To identify DLTs and determine the MTD or MAD for TMZ combined with full-dose
BGB-290
• To select the RP2D for TMZ combined with full-dose BGB 290

Phase 2:
Arm A, Expansion 1 (BGB-290 + RT): Subjects with first-line unmethylated GB
• To assess the efficacy of BGB-290 combined with RT Arm B, Expansion 1
(BGB-290 + RT + TMZ): Subjects with first-line unmethylated GB
• To assess the efficacy of BGB-290 combined with RT and TMZ Arm C, Expansion 1
(BGB-290 + TMZ): Subjects with recurrent/refractory unmethylated GB
• To assess the efficacy of BGB-290 combined with TMZ Arm C, Expansion 2
(BGB-290 + TMZ): Subjects with recurrent/refractory methylated GB
• To assess the efficacy of BGB-290 combined with TMZ

Secondary

Phase 1b, all Arms
• To characterize the PK of BGB-290 in combination with RT and/or TMZ
• To make a preliminary assessment of BGB-290 efficacy in combination with RT
and/or TMZ

Phase 2, all Arms
• To assess safety and tolerability of BGB-290 in combination with RT and/or TMZ
• To characterize the PK of BGB-290 in combination with RT and/or TMZ

This is an open-label, multi-center, multiple-dose, dose-escalation Phase 1b/2
study to determine the safety, pharmacokinetics (PK) and pharmacodynamics of
BGB-290 in combination with RT and/or TMZ with two initial arms and a potential
third arm. In Arm A, BGB-290 will be combined with RT in subjects with
first-line glioblastoma (GB) with unmethylated MGMT promoter (*unmethylated
GB*). In Arm B, depending on the safety of the Arm A combination, BGB-290 will
be combined with both TMZ and RT in subjects with first-line unmethylated GB.
In Arm C, BGB-290 will be combined with TMZ in subjects with
recurrent/refractory GB with methylated or unmethylated MGMT promoter.

The dose escalation phase consists of the following:

Arm A: BGB-290 (60 mg BID) at increasing exposures of 2, 4, and 6 weeks in
combination with RT for 6 to 7 weeks. After RT is completed, subjects will
receive no further study treatment.

Arm B: Depending on the safety of the Arm A combination, the following
combination may be explored: BGB-290 (as determined in Arm A) in combination
with RT for 6 to 7 weeks and increasing doses of TMZ. After RT is completed,
subjects will receive no further study treatment.

Arm C: BGB-290 (60 mg BID) in combination with increasing doses of TMZ
administered on Days 1 to 21 of each 28-day cycle. The dose expansion phase
consists of the following:

Once the safety, tolerability, PK, pharmacodynamic, and preliminary anti-tumor
activity have been reviewed for the dose escalation cohorts of each of the
arms, up to approximately 60 subjects may be enrolled in expansion cohorts for
each of the three arms at a dose level below or equal to the MTD or MAD for
that arm. In Arm C, two expansion cohorts may be opened, one for unmethylated
GB and one for methylated GB. Approximately 60 subjects may be enrolled during
the dose escalation phase, and the four dose expansion cohorts may comprise 240
subjects for a potential
approximate total of 300 subjects enrolled in this study.

Adverse events during and after the treatment period with study drug(s) will be
followed and documented as outlined in Protocol Sections 7.4 and 9. AEs will be
graded according to NCI-CTCAE v4.03. To determine the PK properties of BGB-290,
blood samples will be taken at various time points as outlined in
ProtocolSection 7.8 and Protocol Appendix 1.

Disease status will be assessed using mRANO criteria, v1.1. Subjects will
undergo tumor assessments at screening and then every 8 weeks, or as clinically
indicated.In the absence of unacceptable toxicities or disease progression,
subjects may be offered continued study treatment. Regardless of
discontinuation of one or more study treatment(s), subjects should continue on
study with regular follow-up (Protocol Sections 6.3 and 6.4). Subjects who have
discontinued all study treatments should return to the clinic for an
end-of-treatment (EOT) visit within 7 days of stopping all study treatment.
Subjects in Arms A and B who have completed all study treatments per protocol
will have their EOT visit at the end of the rest phase, 28 days after RT was
completed. After the EOT visit, subjects should have regular follow-up for
safety, efficacy and survival as outlined in Protocol Section 6.4. Subjects
will be followed for survival and further anti-cancer therapy information post
progression via
phone contact (with the subject*s guardian, if applicable) approximately every
12 weeks as per Protocol Appendix 1.

Patients should take their precribed doses of TMZ and BGB-290.

BGB-290:
Arm A, Arm B, and Arm C: 60 mg will be administered PO BID, once in the morning
and once in the evening 12 hours apart, continuously.
Radiation therapy:
Arm A and Arm B: RT will be administered QD × 5 days/week for 6 to 7 weeks with
1.8 to 2 Gy/fraction for a total dose of up to 60 Gy.
Temozolomide:
Arm B and Arm C: flat-dosing will be used for TMZ. The first dose level of 40
mg QD corresponds to 23 mg/m2 assuming an average body surface area of 1.73 m2.
Subsequent dose levels of 80 mg and 120 mg correspond to 46 mg/m2 and 69 mg/m2,
respectively will be administered PO QD.

Furthermore their data of Medical history and demographic data will be
collected They must undergo physicial and vital signs examinations. An
electrocardiogram and MRI scans will be made. Blood and urine will be
collected.

BGB-290 has been studied in nonclinical toxicity and Phase 1 clinical studies.
BGB-290 toxicities are largely consistent with the safety profile shared by
other PARP inhibitors with the important exception that BGB-290 may cause less
myelosuppression. PARP inhibitors, including BGB-290, show at least partial
overlap with the safety profile of RT and/or TMZ. Therefore, subjects of this
study may experience AEs typical for these study treatments at a higher
frequency and/or severity. In addition, subjects may encounter AEs that are
uniquely caused by the novel combination(s). Given the dire prognosis of GB
patients and the limited treatment options, the risk of combining BGB-290 with
RT and/or TMZ appears acceptable in the context of a Phase 1 study with close
monitoring through AE reporting, recording of vital signs and ECGs, clinical
laboratory testing and tumor assessments.
As outlined in Sections 0 and 1.4, scientific rationale and supportive data are
strong for combining PARP inhibitors with RT and/or TMZ in GB. This warrants
evaluation of these combinations in GB patients, as the overall risk-benefit
assessment appears favorable.