Phase I/Ib Dose-escalation of Dinaciclib With Weekly Paclitaxel for Advanced Solid Tumor Malignancies & Assessment of MYC Oncogene Overexpression

This is a single-site, open-label phase I/Ib trial of weekly dinaciclib in combination with
weekly paclitaxel in patients with advanced solid tumor malignancies. Any number of prior
therapies is allowed. Prior treatment with paclitaxel is allowed. Paclitaxel will be
administered weekly by 1-hour intravenous infusion at a fixed dose of 80 mg/m2 during a
28-day repeating cycle. Dinaciclib will be administered weekly by 2-hour intravenous
infusion 24 hours later. Dinaciclib is the investigational agent and will be dose escalated
using a 3+3 design. Only 2 cohorts are planned, although additional cohorts exploring
intermediate doses or specific patient subsets may be added. The starting dinaciclib dose is
7 mg/m2. The primary objective is to define the maximum tolerated dose of dinaciclib when
given weekly in this combination and schedule. The primary endpoint is safety and
tolerability. Secondary objectives include evaluation of the preliminary efficacy of this
combination and determination of pharmacokinetic interactions between dinaciclib and
paclitaxel. Exploratory studies characterizing and correlating the biomarkers relevant to
dinaciclib activity and MYC overexpression with clinical response will be performed.

INCLUSION CRITERIA:

Dose escalation cohorts

1. Histologically or cytologically documented, incurable, unresectable locally advanced,
or metastatic solid tumor malignancy

2. The tumor biopsy is optional in the dose-finding phase of the protocol

3. Patient is male or female and ≥ 18 years of age on the day of signing informed
consent.

4. Patient must have performance status of 0-2 on the ECOG Performance Scale and life
expectancy > 3 months

5. Patient must have evaluable disease

6. Patient must have adequate organ function as indicated by the following laboratory
values:

Hematological

- Absolute neutrophil count (ANC) ≥ 1,500 /μL

- Platelets ≥ 100,000 /μL

- Hemoglobin ≥ 9 g/dL

Renal

- Serum creatinine or calculated creatinine clearance ≤ 1.5 x upper limit of
normal (ULN) OR

- ≥ 60 mL/min for patients with creatinine levels > 1.5 x institutional ULN

Hepatic

- Serum total bilirubin ≤ 1.5 x ULN OR direct bilirubin ≤ ULN for patients with
total bilirubin levels > 1.5 x ULN

- AST (SGOT) and ALT (SGPT) ≤ 2.5 x ULN

Coagulation

- Prothrombin time (PT)/INR ≤ 1.2 x ULN

- Partial thromboplastin time (PTT) ≤ 1.2 x ULN

Metabolic

- Potassium, Calcium, Phosphorus in normal range

- Uric Acid in normal range

7. Female patient of childbearing potential must have a negative serum or urine
pregnancy test β-hCG and agree to the use of effective methods of contraception while
on study.

8. Patient has voluntarily agreed to participate by giving written informed consent

9. Prior taxane in the adjuvant or metastatic setting is allowed

10. Any number of prior lines of chemotherapy in the metastatic setting is allowed

11. Concomitant use of bisphosphonates is allowed

12. Patients with stable and clinically insignificant CNS disease are allowed, patients
must be off steroids with no new CNS symptoms or findings on radiographic imaging

Dose expansion cohort

1. Histologically documented metastatic or locally advanced unresectable breast cancer
that is ER and PR ≤ 10% expression and does not over-express HER2 protein (IHC 0, 1+,
or 2+and FISH < 2.0)

2. Patient must consent to a biopsy of a site of disease unless the only site of disease
is lung/pleura

3. Patient must have measureable disease

4. All other inclusion criteria per the dose escalation cohorts

EXCLUSION CRITERIA:

Both dose escalation and dose expansion cohorts

1. Patient who has had radiotherapy or hormonal therapy within 2 weeks, chemotherapy
within 3 weeks or 5 half-lives, whichever is shorter (6 weeks for nitrosoureas,
mitomycin C or bevacizumab), or who has not recovered from toxicity due to previous
agents administered. If the patient has residual toxicity from prior treatment,
toxicity must be ≤ Grade 1.

2. Patients less than 4 weeks post major surgical procedure (all surgical wounds must be
fully healed). For the purpose of this criterion, a major surgical procedure is
defined as one requiring the administration of general anesthesia.

3. Patient is currently participating or has participated in a study with an
investigational compound or device within 30 days of Study Day 1

4. Patient has known active CNS metastases and/or carcinomatous meningitis. However,
patients with CNS metastases who have completed a course of therapy would be eligible
for the study provided they are clinically stable for at least 1 month prior to entry
as defined as: (1) no evidence of new or enlarging CNS metastasis (2) off steroids.
Patients with clinically insignificant brain metastases that do not require treatment
are eligible.

5. Patient has a primary central nervous system tumor

6. Patient has known hypersensitivity to the components of study drug or its analogs.
Patients who have had a hypersensitivity reaction to paclitaxel or products
formulated with Cremophor® EL (polyoxyethylated castor oil) should not be enrolled in
this study.

7. Patient has a history or current evidence of clinically significant heart disease
including:

- Clinically significant congestive heart failure, unstable angina pectoris

- Clinically significant cardiac arrhythmia Myocardial infarction during the last
6 months, and/or a current ECG tracing that is abnormal in the opinion of the
treating Investigator QTc prolongation > 450 msec (Bazett's Formula)

- Congenitally long QT syndrome, and/or current anti-arrhythmic therapy, has
received any marketed or experimental compound in the last 4 weeks prior to
entering the study with possible or known effects of QT prolongation, or
cumulative high-dose anthracycline therapy.

8. Patient with evidence of clinically significant bradycardia (HR < 50), or a history
of clinically significant bradyarrhythmias such as sick sinus syndrome, 2nd degree AV
block (Mobitz Type 2), Patient with uncontrolled hypertension (≥ 140/90 mmHg).
Patients who are controlled on antihypertensive medication will be allowed to enter
the study.

9. Patient has a history or current evidence of any condition, therapy, or lab
abnormality that might confound the results of the study, interfere with the
patient‟s participation for the full duration of the study, or is not in the best
interest of the patient to participate, in the opinion of the treating investigator.

10. Patient has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial

11. Patient is, at the time of signing informed consent, a regular user of any illicit
drugs or had a recent history (within the last year) of drug or alcohol abuse.

12. Patient is pregnant or breastfeeding, or expecting to conceive or father children
within the projected duration of the study

13. Patient is known to be Human Immunodeficiency Virus (HIV)-positive

14. Patient has known history of active Hepatitis A, B, or C

15. Patient has symptomatic ascites or pleural effusion, a patient who is clinically
stable following treatment for these conditions is eligible

16. Patient is receiving treatment with oral corticosteroids (physiologic replacement
doses and inhaled corticosteroids are permitted)

17. Patient has baseline neuropathy of ≥ grade 2

18. Patients who have known allergic reactions to paclitaxel or IV contrast dye despite
standard prophylaxis

19. Patients who require medications that are strong CYP3A4 inhibitors or inducers.
Patients who have discontinued any of these medications must have a wash-out period
of at least 5 days or at least 5 half-lives of the drug (whichever is longer) prior
to the first dose of dinaciclib.

20. Patients requiring warfarin therapy, low molecular weight heparin is permitted