This is an open-label, dose escalation study to evaluate the safety, tolerability,
pharmacokinetics, and preliminary evidence of antitumor activity of CPO-100 administered
intravenously in cycles of 3 weekly doses with 1 week rest (1 cycle = 4 weeks) in adult
patients with advanced solid tumors. The second part of the study will further evaluate the
safety and tolerability of as well as antitumor activity at the recommended dose from the
dose escalation phase.
This is a phase 1, multicenter, open-label, dose escalation study to evaluate the safety,
tolerability, pharmacokinetics (PK), and preliminary evidence of antitumor activity of
CPO-100 administered intravenously in cycles of 3 weekly doses with 1 week rest (1 cycle = 4
weeks) in adult patients with advanced solid tumors.
The study has two parts. Part A is a dose-escalation phase with a modified "3+3" design in
patients with metastatic or unresectable advanced solid tumors to determine the recommended
phase 2 dose (RP2D) and schedule, and to evaluate the safety, tolerability and PK as a single
agent. Two patients will be enrolled at each of the first 2 dose levels and observed for
safety during the first cycle. If there are no ≥Grade 2 treatment emergent adverse events
(TEAE) that may be attributed to the study drug during Cycle 1 for any of the patients in the
first two dose levels, the 3rd dose level and beyond will follow the traditional 3+3 design.
Dose escalation during the "3+3" period for each subsequent cohort of patients will be guided
by the incidence of CPO-100-related adverse events (AE) as graded by National Cancer
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) CTCAE v5.0 in the
first 4 weeks of dosing [the Dose Limiting Toxicity (DLT) evaluation period].
After the Maximum Tolerated Dose (MTD) of weekly dosing schedule has been established, a
recommended Phase 2 dose will be selected based on evaluation of the PK, and safety and
tolerability profile by the Safety Review Committee (SRC).
Part B expansion phase will further evaluate the safety and tolerability as well as the
preliminary antitumor activity at the selected RP2D. Four cohorts of patients are included in
Part B:
- Cohort 1: patients with taxane naïve advanced solid tumors of gastric, head and neck,
lung, and ovarian
- Cohort 2: patients with taxane naïve advanced breast cancer
- Cohort 3: patients with taxane naïve advanced prostate cancer
- Cohort 4: patients with either ovarian or/and breast cancer who have failed prior taxane
treatment (ie, either progressed on a taxane regimen or within 6 months of receiving a
taxane regimen).
The taxane naïve patient population is defined as patients who have not received taxane or
taxane based therapies for their metastatic diseases or patients who had suboptimal taxane
exposure defined as having received less than 2 cycles of taxane or taxane based therapies
due to intolerability for their metastatic diseases. Patients who have received taxane or
taxane based therapies for their neoadjuvant treatment or patients who have received taxane
or taxane based therapies for their adjuvant treatment without disease progression during
treatment are also considered taxane naïve, as long as they have not received taxane or
taxane based therapies to treat the metastatic diseases.
It is estimated that up to 42 patients can be enrolled in Part A. The exact number of
patients will depend on the number of dose levels tested. A total of 60 patients, 15 patients
in each cohort will be enrolled in Part B.
The total duration of the study is estimated to be approximately 4 years. Patients may
continue receiving CPO-100 until criteria for withdrawal are met. Patients deriving clinical
benefit may continue to receive study medication for as long as they are benefiting from
treatment. In the event the study closes or terminates while patients are still benefiting
from and receiving CPO-100, every effort will be made to continue drug supply.
Inclusion Criteria - Part A and B:
1. Presence of a pathologically documented (histology or cytology) locally advanced or
metastatic solid tumor cancer.
2. Patients has failed at least 2 lines of conventional systemic therapy or have no other
standard of care therapies available for their cancer. For a prostate cancer patient,
adenosine triphosphate (ADT) alone (GnRH agonist, GnRH antagonist, or surgical
orchiectomy) would count towards a line of conventional systemic therapy.
3. Male or female patients18 years of age or older.
4. ECOG (Eastern Cooperative Oncology Group) performance status (PS) of 0, 1 or 2
5. Having at least one measurable target lesion present and documented by RECIST 1.1 for
each cancer other than prostate cancer. Patients with prostate cancer may be enrolled
with non-measurable disease providing the patient with a prostate-specific antigen
(PSA) increase that is ≥25% and ≥2 ng/mL above the nadir, which is confirmed by a
second value ≥3 weeks later, or 2 or more new bone lesions on imaging.
6. Adequate major system function defined as:
1. Bone marrow reserve:
Absolute neutrophil count (ANC) ≥1.5 x109/L Platelet count ≥ 100 x109/L
Hemoglobin ≥9 g/dL without transfusion (the patient needs to be transfusion
independent)
2. Hepatic function:
Total bilirubin ≤ upper limit of normal (ULN) (unless the subject has Grade 1
bilirubin elevation due to Gilbert's disease or a similar syndrome involving slow
conjugation of total bilirubin); And aspartate aminotransferase (AST) / serum
glutamic oxaloacetic transaminase (SGOT) and/or alanine aminotransferase (ALT) /
serum glutamic pyruvic transaminase (SGPT) ≤ 1.5 x ULN with alkaline phosphatase
≤2.5 x ULN.
3. Renal function:
Normal serum creatinine ≤1.5 mg/dL (133 μmol/L) OR calculated creatinine
clearance ≥50 mL/min. (Cockcroft - Gault formula)
4. Coagulation:
Adequate coagulation parameters defined as International Normalization Ratio (INR) ≤2.
7. Adequate methods of contraception for female patients of reproductive potential during
the study and for at least 6 months following last dose. Male patients with female
partners of childbearing potential and women patients of childbearing potential are
required to use two forms of acceptable contraception, including 1 barrier method,
during their participation in the study and for at least 3 months following last dose.
Male patients must also refrain from donating sperm during their participation in the
study.
8. Life expectancy ≥3 months.
9. Willingness and ability to comply with study and follow-up procedures.
10. Ability to understand the nature of this study and give written informed consent.
Additional Inclusion Criteria for the dose expansion cohort - Part B
1. Pathologically confirmed (histology or cytology) of the following cancer types:
1. Cohort 1: taxane naïve advanced/metastatic gastric cancer, lung cancer, head and
neck cancer, or ovarian cancer;
2. Cohort 2: taxane naïve advanced/metastatic breast cancer;
3. Cohort 3: taxane naïve advanced/metastatic prostate cancer.
4. Cohort 4: advanced/metastatic breast or ovarian cancer patients who have either
progressed on a taxane or have developed progressive disease within 6 months of
receiving a taxane;
2. With the exception of Cohort 4 above, taxane naïve patients must not have received
taxane or taxane based therapies for their metastatic diseases. Patients who had
suboptimal taxane exposure defined as having received less than 2 cycles of taxane or
taxane based therapies due to intolerability for their metastatic diseases, patients
who have received taxane or taxane based therapies for their neoadjuvant treatment or
patients who have received taxane or taxane based therapies for their adjuvant
treatment without disease progression during treatment are also considered taxane
naïve, as long as they have not received taxane or taxane based therapies to treat the
metastatic diseases.
Exclusion Criteria - Part A and B
1. Most recent chemotherapy ≤14 days or have residual NCI CTCAE greater than Grade 1
chemotherapy-related side effects, with the exception of alopecia and Grade 2
neuropathy.
2. Use of any experimental drug ≤28 days or 5 half-lives (whichever is shorter) prior to
the first dose of CPO-100. For study drugs for which 5 half-lives is ≤28 days, a
minimum of 14 days between termination of the study drug and administration of CPO-100
is required.
3. Wide field radiotherapy (including therapeutic radioisotopes such as strontium 89)
administered ≤28 days or limited field radiation for palliation ≤7 days prior to
starting study drug or has not recovered from side effects of such therapy.
4. Major surgical procedures ≤28 days of beginning study drug, or minor surgical
procedures ≤7 days. No waiting required following port-a-cath placement.
5. Previously untreated brain metastases. Patients who have received radiation or surgery
for brain metastases are eligible if therapy was completed at least 2 weeks previously
and there is no evidence of central nervous system disease progression, and no
requirement for chronic corticosteroid therapy.
6. Leptomeningeal metastases or spinal cord compression due to disease.
7. Known serious hypersensitivity reactions to docetaxel or life-threatening toxicity due
to prior exposure to docetaxel
8. Pregnant or lactating.
9. Acute or chronic liver, renal, or pancreatic disease that in the opinion of the
investigator would put the patient at unjustified increased risk by participating in
this study or could interfere with the interpretation of the study results.
10. Other systemic disease that in the opinion of the investigator would put the patient
at unjustified increased risk by participating in this study or could interfere with
the interpretation of the study results.
11. Any of the following cardiac diseases currently or within the last 6 months:
- Left ventricular ejection fraction (LVEF) <50% as determined by multiple gated
acquisition (MUGA) scan or echocardiogram (ECHO)
- Corrected QT (QTc) interval >470 ms (average of 3 tracings) on screening
electrocardiogram (ECG)
- Unstable angina pectoris
- Congestive heart failure according to the New York Heart Association (NYHA) ≥
Grade 2)
- Acute myocardial infarction
- Conduction abnormality not controlled with pacemaker or medication
- Significant ventricular or supraventricular arrhythmias. (Patients with chronic
rate-controlled atrial fibrillation in the absence of other cardiac abnormalities
are eligible.)
12. Inadequately controlled hypertension (ie, systolic blood pressure (SBP) >180 mmHg or
diastolic blood pressure (DBP) >100 mmHg). Subjects with values above these levels
must have their blood pressure (BP) controlled with medication prior to starting
treatment.
13. Serious active infection at the time of treatment, or another serious underlying
medical condition that that in the judgment of the investigator would impair the
ability of the patient to receive protocol treatment.
14. History of seropositive status for human immunodeficiency virus (HIV) at any time
before the start of treatment as determined by presence of anti-HIV-1 or anti-HIV-2
antibodies. Testing for seropositive status during Screening will be at the discretion
of the investigator in patients without previously reported results.
15. Active hepatitis B, or hepatitis C infection.
- Patients will be tested for hepatitis C virus (HCV) and hepatitis B virus (HBV)
at Screening.
- Patients with hepatitis B (HepBsAg+) who have controlled infection (serum
hepatitis B virus DNA level is below the limit of detection by PCR) may be
enrolled into the study. Subjects with controlled infections must undergo
periodic monitoring of HBV DNA per treating physician.
- Patients with hepatitis C (HCV Ab+) who have controlled infection (undetectable
HCV RNA by PCR either spontaneously or in response to a successful prior course
of anti-HCV therapy) may be enrolled into the study. Patients with controlled
infections must undergo periodic monitoring of HCV RNA per treating physician.
16. Presence of other active cancers, or history of treatment for invasive cancer ≤3
years. Patients with Stage I cancer who have received definitive local treatment and
are considered unlikely to recur are eligible. All patients with previously treated in
situ carcinoma (ie, non-invasive) are eligible, as are patients with history of
non-melanoma skin cancer.
17. Psychological, familial, sociological, or geographical conditions that do not permit
compliance with the protocol.
18. Routine use of corticosteroids or erythrocyte-stimulating factors as well as
prophylactic use of colony-stimulating factors.
19. Use of any CYP3A4 inhibitor or inducer drug ≤28 days or 5 half-lives (whichever is
shorter) prior to the first dose of CPO-100. For CYP3A4 drugs for which 5 half-lives
is ≤28 days, a minimum of 14 days between discontinuation of the drug and
administration of CPO-100 is required.
20. Use of herbal preparations/medications including, but are not limited to: St. John's
wort, kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe,
saw palmetto, and ginseng. A minimum of 14 days between discontinuation of the herbal
preparation/medications and administration of CPO-100 is required.
