| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027475 |
| E.1.2 | Term | Metastatic breast cancer |
| E.1.2 | System Organ Class | 100000020826 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase 1
• To assess the safety and tolerability of PD 0332991 in combination
with letrozole in postmenopausal women with ER+, HER2 negative ABC.
Phase 2
• To assess the effect of letrozole plus PD 0332991 and of letrozole
alone on progression-free survival (PFS) in the first-line treatment of
ER+, HER2 negative ABC in postmenopausal women prospectively
identified to have tumors with CCND1 amplification and/or loss of p16 |
|
| E.2.2 | Secondary objectives of the trial |
•Evaluate PK of PD 0332991 & letrozole when administered in
combination
•Characterize effects of PD 0332991 on QTc
•Document anti-tumor activity of PD 0332991 in combination with
letrozole
•Explore relationship between expression of baseline genes of interest &
protein levels with tumor response
•Explore relationship between germline polymorphism in CYP19A1 &
CCND1 genes & tumor response
Phase 2
•Assess secondary measures of efficacy for PD 0332991 plus letrozole &
for letrozole alone
•Assess safety & tolerability of PD 0332991 plus letrozole & of letrozole
alone
•Assess impact of PD 0332991 plus letrozole & of letrozole alone on
patient reported outcomes of pain
•Explore relationship between copy number & expression of baseline
genes of interest & protein levels including Rb, p16/INK4A, CCND1,
CDK4, CDK6, & Ki67 markers with tumor response
•Explore relationship between germline polymorphism in CYP19A1 &
CCND1 genes & tumor response |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must meet all of the following inclusion criteria to be eligible
for enrollment into the study:
1.Histologically or cytologically proven diagnosis of adenocarcinoma of
the breast with evidence of 1) locally recurrent disease not amenable to
resection or radiation therapy with curative intent, or 2) metastatic
disease.
2.ER positive tumor. Positivity is defined either as ≥10 fmol of H to the
power of 3 -estrogen binding per mg of cytosol protein for dextran
coated charcoal and sucrose density methods, or ≥0.10 fmol of H to the
power of 3 -estrogen binding per mg of DNA for IF/EIA technique. In
case of use of immunohistochemistry, the report should mention positive
receptor status according to the standards of the laboratory.
3.HER2 negative breast cancer by FISH or IHC.
4.Paraffin-embedded tumor block(s) available for centralized
assessment of Rb and other cell cycle-related proteins. Phase 2 Part 2
only: CCND1 amplification and/or loss of p16 as determined by the
central laboratory.
5.Measurable disease according to RECIST or bone-only disease (Phase 2
only). Previously irradiated lesions are deemed measurable only if
progression is documented at the site after completion of radiation.
6. Females, 18 years of age or older
7.Postmenopausal status defined as:
•Prior bilateral surgical oophorectomy
•Amenorrhea and age ≥ 60 years
•Age < 60 years and amenorrhea for 12 or more months in the absence
of chemotherapy, tamoxifen, toremifene, or ovarian suppression and FSH
and estradiol in the postmenopausal ranges
8.Eastern Cooperative Oncology Group (ECOG)Performance status 0 or 1.
9.Resolution of all acute toxic effects of prior therapy or surgical
procedures to CTCAE grade ≤1 (except alopecia or other toxicities not
considered a safety risk for the patient).
10.Adequate organ function as defined by the following criteria:
•Absolute neutrophil count (ANC) ≥ 1500/μL
•Platelets ≥ 100,000/μL
•Serum aspartate transaminase (AST) and serum alanine transaminase
(ALT) ≤3 x upper limit of normal (ULN), or AST and ALT ≤5 x ULN if liver
function abnormalities are due to underlying malignancy
•Total serum bilirubin ≤ 1.5 x ULN regardless of liver involvement
secondary to tumor. Inclusion of patients with increased serum indirect
bilirubin due to Gilbert's syndrome is permitted.
•Serum creatinine ≤ 1.5 x ULN
•QTc ≤470 msec (based on the mean value of the triplicate ECGs)
11. Evidence of a personally signed and dated informed consent document indicating that the
subject (or a legal representative) has been informed of all pertinent aspects of the study.
12. Subjects who are willing and able to comply with scheduled visits, treatment plan,
laboratory tests, and other study procedures. |
|
| E.4 | Principal exclusion criteria |
Subjects presenting with any of the following will not be included in the
study:
1. Brain metastases (even if treated and stable), spinal cord
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compression, carcinomatous meningitis, or leptomeningeal disease.
2. Major surgery within 3 weeks of first study treatment.
3. Prior treatment with:
• Any anti-cancer therapies for advanced disease, with the exception of
radiation
therapy to < 25% of bone marrow at least 2 weeks prior to study
treatment initiation
• (neo)adjuvant letrozole with disease recurrence ≤12 months (Phase 2
only)
• Any CDK inhibitor
4. Current treatment with:
• Any anti-cancer therapies for advanced disease
• Any experimental treatment on another clinical trial
• Therapeutic doses of anticoagulant. Low dose anticoagulants for deep
vein
thrombosis prophylaxis are allowed. Low molecular weight heparin is
allowed.
Aspirin is permitted.
5. Current use or anticipated need for:
• food or drugs that are known strong CYP3A4 inhibitors (i.e. grapefruit
juice,
verapamil, ketoconazole, miconazole, itraconazole, posaconazole,
erythromycin,
clarithromycin, tilithromycin, indinavir, saquinavir, ritonavir, nelfinavir,
lopinavir,
atazanavir, amprenavir, fosamprenavir, nefazodone, diltiazem, and
delaviridine) – for
both Phases 1 and 2
• drugs that are known strong CYP3A4 inducers (i.e. carbamazepine,
dexamethasone, felbamate, omeprazole, phenobarbital, phenytoin,
primidone, rifabutin, rifampin, rifapentin, clevidipine, and St. John's
Wort) – for Phase 1 only.
6. Diagnosis of any secondary malignancy within the last 3 years, except
for adequately treated basal cell or squamous cell skin cancer, or
carcinoma in situ of the cervix
7. Any of the following in the previous 6 months: myocardial infarction,
severe/unstable angina, ongoing cardiac dysrhythmias of NCI CTCAE
grade ≥ 2, atrial fibrillation of any grade, coronary/peripheral artery
bypass graft, symptomatic congestive heart failure, cerebrovascular
accident including transient ischemic attack, or symptomatic pulmonary
embolism.
8. Active inflammatory bowel disease or chronic diarrhea. Short bowel
syndrome. Upper gastrointestinal surgery including gastric resection.
9. Known hypersensitivity to letrozole or to any of its excipients
10. Known human immunodeficiency virus infection
11. Other severe acute or chronic medical or psychiatric condition or
laboratory abnormality that may increase the risk associated with study
participation or investigational product administration or may interfere
with the interpretation of study results and, in the judgment of the
investigator, would make the subject inappropriate for entry into this
study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1:
Overall safety profile of PD 0332991 in combination with letrozole, including dose limiting toxicities (DLTs).
Phase 2:
Progression free survival (PFS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Phase 1:
Plasma pharmacokinetic parameters of PD 0332991 and letrozole.
QTc interval.
Objective tumor response (OR).
Clinical benefit response (CBR).
Tumor tissue levels including but not limited to Rb, p16/INK4A, CCND1, CDK4, CDK6,
and Ki67.
Germline polymorphism in CYP19A1 and CCND1 genes.
Phase 2:
OR.
CBR.
Time to tumor progression (TTP).
Duration of response (DR).
Overall survival (OS).
Overall safety profile.
Patient Reported Outcome (PRO) of pain using the modified Brief Pain Inventory – short
form (mBPI-sf).
Tumor tissue levels including but not limited to Rb, p16/INK4A, CCND1, CDK4, CDK6,
and Ki67 and copy number of CCND1 and p16.
Germline polymorphism in CYP19A1 and CCND1 genes. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 15 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 45 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Belgium |
| Canada |
| Denmark |
| France |
| Germany |
| Hungary |
| Ireland |
| Italy |
| Korea, Republic of |
| Russian Federation |
| South Africa |
| Spain |
| Ukraine |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 8 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 25 |
| E.8.9.2 | In all countries concerned by the trial years | 10 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 15 |
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