Safety,Tolerability and MTD KA2507 (HDAC6 Inhibitor) in Patients With Solid Tumours

The aim of the study is to evaluate the safety/tolerability, pharmacokinetic, and
pharmaco-dynamic effects of KA2507 and establish the maximum tolerated dose (MTD). Patients
with PD-L1 expressing solid tumors which have relapsed or are refractory to prior treatment
will be eligible to participate in this study.

Following completion of the multiple ascending dose study, the protocol may be amended to
include expansion cohorts in patients with melanoma and/or other solid tumors.

This is a multiple ascending dosing (MAD) study of up to 6 treatment regimens cohorts based
on using a 3+3 design (up to 36 patients overall). The principal objective is to establish
the maximum tolerated dose, safety, tolerability and pharmacokinetic (PK) profile in blood
and urine of this HDAC6 inhibitor in patients with solid tumors and to explore effects on
pharmacodynamic markers of target engagement and response to treatment.

Daily/twice daily doses will be given as open label monotherapy. A review of safety and PK
data will be conducted once the last patient in each cohort reaches day 28 of treatment. The
review will confirm the dose to be used for the subsequent cohort. Dose escalation will be
continued until the MTD is reached. Upon completion of the dose escalation phase of the
study, dose expansion phases will be planned.

Patients responding to treatment may elect to remain on therapy until disease progression,
death or the investigator decides to stop treatment.

Inclusion Criteria:

1. Age ≥18 years at the screening visit.

2. Patients with histologically or cytologically documented, confirmed diagnosis of
advanced malignancy, whose disease failed to respond to or progressed after standard
therapy or they could not tolerate standard therapy.

3. Measurable or evaluable disease according to RECIST v1.1.

4. ECOG performance status of 0 or 1.

5. Predicted life expectancy ≥12 weeks.

6. For men and women of child-bearing potential, willing to use adequate contraception
(i.e., latex condom, cervical cap, diaphragm, abstinence, etc.) for the entire
duration of the study.

1. If female, must be either postmenopausal, sterilised or, if sexually active, effectively
practicing an acceptable method of contraception (either oral, parenteral, or implantable
hormonal contraceptives, intrauterine device or barrier and spermicide). Subjects must
agree to use adequate contraception during the study and for at least 12 weeks (or longer
as per local requirement) after the last dose of study treatment.

2. Male subjects agree to ensure that they or their female partner(s) use adequate
contraception during the study and for at least 12 weeks (or longer as per local
requirement) after the subject receives their last dose of study treatment.

Exclusion Criteria:

1. Patients are not able to provide written informed consent to study participation

2. Patients who have been treated with most recent radiotherapy, hormonal therapy,
immunotherapy, chemotherapy or investigational drugs within ≤21 days or 5 half-lives
(whichever is shorter) from enrolment (screening), and/or who have any unresolved NCI
Common Terminology Criteria of Adverse Events (CTCAE) v4.03 > Grade 1
treatment-related side effect (with the exception of alopecia).

3. Patient has anemia due to HbS or HbC disease, alpha or beta thalassaemia

4. Patient has Glucose-6-phosphate deficiency

5. Patient has known or suspected history of cytochrome b5-MetHb-reductase pathway
deficiency

6. Persons of Navajo, Athabaska Alaskan or Siberian Yakutsk descent

7. Patient has untreated severe hypothyroidism

8. Patient has laboratory estimations indicating organ system dysfunction:

1. Absolute neutrophil count (ANC) <1.5 X 109/L

2. Platelets <100 X 109/L

3. Hemoglobin <9g/dL

4. Total bilirubin >1.5 mg/dL

5. ALT and AST >3.0 times the ULN if no liver involvement or >5 times the ULN with
liver involvement.

6. Calculated creatinine clearance <60mL/min estimated using the Cockcroft-Gault
equation:

• Cockcroft-Gault equation: creatinine clearance = (140 - age in years) x (wt in
kg)) x 1.23) / (serum creatinine in micromol/l) [For women multiply the result of
calculation by 0.85].

9. Major surgery (excluding placement of vascular access) ≤21 days from beginning of the
study drug or minor surgical procedures ≤7 days. No waiting is required following
implantable port and catheter placement.

10. Any of the following cardiac criteria:

1. Congestive heart failure (CHF), grade III or IV per New York Heart Association
(NYHA) classification

2. Symptomatic cardiomyopathy

3. > Class II Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy

4. Unstable angina or new-onset angina

5. QTcF interval >470 ms on screening ECG.

9. Severe or uncontrolled systemic diseases including uncontrolled hypertension, active
bleeding diatheses 10. Any evidence of active infection including active Hepatitis B,
Hepatitis C or human immunodeficiency virus 11. The patient has concurrent severe and/or
uncontrolled medical disease that could compromise participation in the study (i.e.,
uncontrolled diabetes, severe infection requiring active treatment, severe malnutrition,
chronic severe liver or renal disease, uncontrolled hypertension, active bleeding
diatheses).

12. Active infection requiring IV antibiotics within two weeks prior to treatment, or
evidence of TB infection.

13. Hepatitis B, Hepatitis C or human immunodeficiency virus 14. Previously untreated brain
metastases. Patients who have received radiation or surgery for brain metastases are
eligible if therapy was completed at least 3 weeks previously and there is no evidence of
central nervous system disease progression, mild neurologic symptoms, and no requirement
for chronic corticosteroid therapy.

15. Lactating, breastfeeding, or positive pregnancy test for female patients of
child-bearing potential.

16. The patient is unable to swallow capsules and/or has a surgical or anatomical condition
that precludes swallowing and absorbing oral medication on an ongoing basis (for oral
therapy only).

17. Patients with prior stem cell transplantation or solid organ transplantation.

18. History of other malignancies (except for adequately treated basal or squamous cell
carcinoma or carcinoma in situ) within the last 3 years.

17. Any other condition that would, in the investigator's judgment, contraindicate the
patient's participation in the clinical study due to safety concerns or compliance with
clinical study procedures.