ARQ 751 as a Single Agent or in Combination With Other Anti-Cancer Agents, in Solid Tumors With PIK3CA / AKT / PTEN Mutations

AKT inhibitor may decrease or arrest growth of cancer cells that depends on the presence of a
protein called AKT. A number of genes, namely, PIK3CA, AKT and PTEN, may cause the AKT to
behave abnormally, so by blocking the action of these genes on AKT with the drug like ARQ
751, the cancer spread may be stopped or slowed down. Paclitaxel and fulvestrant are standard
anticancer agents, paclitaxel is given to destroy cancer cells and fulvestrant to lower the
amount of estrogen the body makes. ARQ 751 in combination with paclitaxel or fulvestrant may
potentiate effect of a single therapy in tumors driven by PIK3CA/AKT/PTEN mutations.

Inclusion Criteria

1. Signed written informed consent granted prior to initiation of any study-specific
procedures

2. 18 years of age and older

3. Histologically and/or cytologically documented diagnosis of a selected tumor type that
is locally advanced, inoperable, metastatic or recurrent (including but not restricted
to breast cancer, TNBC [triple negative]; HR-positive [HR+]/HER2-negative [HER2-] or
endometrial cancer)

4. Documented PIK3CA, AKT or known actionable PTEN mutations by genetic testing

5. For combination arms; eligible for paclitaxel or fulvestrant therapy as per
Investigator assessment

6. Failure to respond to standard therapy, or for whom standard or curative therapy does
not exist or is not tolerable

- No more than 3 prior systemic regimens for the advanced disease with confirmed
disease progression

- Neoadjuvant and adjuvant chemotherapy are considered one regimen if they are a
continuation of the same regimen with interval debulking surgery

- If the subject is refractory or has disease progression within 6 months after
completion of the adjuvant treatment, then the adjuvant treatment should be
considered as the line of treatment rather than an adjuvant therapy.

- Endocrine (hormonal) therapy does not count toward total lines of therapy

- Maintenance therapy is considered part of the preceding regimen if one or more of
the same drugs are continued

7. Has at least one measurable target lesion according to RECIST v. 1.1

8. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1

9. Adequate organ function as indicated by the following laboratory values. (All
laboratory tests must be obtained within 14 days prior to the first dose of study
treatment):

1. Hematological

- Absolute neutrophil count (ANC) ≥ 1.5 x 10⁹/L

- Platelet count (Plt) ≥ 100 x 10⁹/L

- Hemoglobin (Hb) ≥ 9 g/dL

- International normalized ratio (INR) 0.8 to upper limit of normal (ULN) or ≤
3 for subjects receiving anticoagulant therapy such as Coumadin or heparin

2. Renal

- Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 60
mL/min/1.73 m2 for subjects with serum creatinine levels > 1.5 x
institutional ULN

3. Hepatic

- Total bilirubin ≤ 1.5 x ULN

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x
ULN or ≤ 5 x ULN for subjects with known liver metastases

4. Metabolic

- Glycated hemoglobin (HbA1c) ≤ 8% (≤ 64 mmol/mol)

10. If a subject is currently receiving bisphosphonates or any other drug for treatment of
osteoporosis, treatment-induced bone loss and metastases to bone, the subject must
have received the bisphosphonates for at least four weeks prior to the first dose of
study treatment

• Initiation of bisphosphonates or similar agents during the study may be allowed
provided the subject completes the first cycle of treatment without any dose limiting
toxicity (DLT) and the Investigator rules out tumor progression

11. Male or female subjects of child-producing potential must agree to use double-barrier
contraceptive measures, oral contraception, or avoidance of intercourse during the
study and for 90 days after the last dose of study treatment

12. Women of childbearing potential must have a negative serum pregnancy test. "Women of
childbearing potential" is defined as sexually mature women who have not undergone a
hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive
months prior to the first dose of study treatment

Exclusion Criteria

1. Anti-cancer therapy, such as chemotherapy, immunotherapy, hormonal therapy, targeted
therapy, or investigational agents within five half-lives or four weeks, whichever is
shorter, prior to administration of the first dose of study treatment (five half-lives
or six weeks, whichever is shorter)

- To be eligible for study treatment, toxicity from prior treatment(s) must recover
to Grade ≤ 1, except for alopecia

- Concurrent systemic high-dose corticosteroids (in dosing exceeding 10 mg QD of
prednisone equivalent) when used intermittently in an antiemetic regimen, for
central nervous system (CNS) metastases management, or as a part of the
premedication regimen are allowed

2. Radiation therapy within four weeks, or palliative radiation therapy within two weeks,
prior to administration of the first dose of study treatment

- To be eligible for study treatment, radiation therapy-related toxicity must
recover to Grade ≤ 1 prior to administration of the first dose of study treatment

- Concurrent palliative radiotherapy for local pain-control or prevention of
fracture (for known bone metastases) may be allowed provided the subject
completes the first cycle of treatment, does not meet criteria of progressive
disease, and treated lesions will not be included in the target/non-target lesion
assessment

3. Major surgical procedure within four weeks prior to administration of the first dose
of study treatment

• To be eligible for the study treatment, all surgical wounds must be fully healed,
and any surgery-related adverse events must recover to Grade ≤ 1.

4. Unable or unwilling to swallow the complete daily dose of ARQ 751

5. Previous treatment with

- AKT inhibitors (e.g., ARQ 092, MK-2206, GSK2141795, AZD5363; prior treatment with
PI3K or mTOR inhibitor are allowed)

- Prior taxane therapy for the advanced, metastatic disease

- Known prior allergic reaction to or severe intolerance of paclitaxel or
fulvestrant. Intolerance is defined as a serious adverse event, a grade 3 or 4 AE
per CTCAE v.4.03, or permanent treatment discontinuation

6. History of Type 1 or 2 diabetes mellitus requiring regular medication (other than oral
hypoglycemic agents) or fasting glucose ≥ 160 mg/dL at Screening visit

7. Significant gastrointestinal disorder(s) that could, in the opinion of the
Investigator, interfere with the absorption, metabolism, or excretion of ARQ 751
(e.g., inflammatory bowel disease, Crohn's disease, ulcerative colitis, extensive
gastric resection)

8. Known untreated or active CNS metastases and/or carcinomatous meningitis

• To be eligible for the study treatment, subjects must have stable disease ≥ 1 month,
confirmed by magnetic resonance imaging (MRI) or computed tomography (CT) scan, and
have CNS metastases well controlled by low-dose steroids, anti-epileptics, or other
symptom-relieving medications

9. History of myocardial infarction (MI) or New York Heart Association (NYHA) Class II-IV
congestive heart failure within 6 months of the administration of the first dose of
study treatment (MI occurring > 6 months of the first dose of study treatment will be
permitted); Grade 2 or worse conduction defect (e.g., right or left bundle branch
block)

10. A heart rate corrected QT (QTc) interval ≥ 480 msec, using the Fridericia's formula
QTcF

11. Left ventricular ejection fraction (LVEF) <50% as determined by Multiple Gated
Acquisition (MUGA) scan or echocardiogram (ECHO) in subjects who received prior
treatment with anthracyclines

12. Concurrent severe and/or uncontrolled illness not related to cancer and/or social
situation that would limit compliance with study requirements, including but not
limited to:

- Psychiatric illness, substance abuse

- Ongoing or active known infection, including human immunodeficiency virus (HIV)
infection, hepatitis B or C virus

- Significant pulmonary dysfunction, including pneumonitis, interstitial lung
disease (ILD), idiopathic pulmonary fibrosis, cystic fibrosis, severe COPD

- Peripheral neuropathy grade ≥2 (Arm B, ARQ 751+paclitaxel)

- Bleeding diathesis, thrombocytopenia or coagulation disorders (Arm C, ARQ
751+fulvestrant)

- Thrombotic/coagulation disorders within 6 months prior to the first dose of study
treatment unless stable on anticoagulation for > 3 months

13. Active or history of other malignancy other than the current cancer within 2 years of
the first dose of study treatment, with the exception of carcinoma in-situ of the
cervix, basal cell carcinoma, and superficial bladder tumors curatively treated

14. Blood transfusion or administration of growth factors within 5 days prior to a blood
draw being used to confirm eligibility

15. Pregnant or breastfeeding