Overview
This is a multi-center, open-label, phase Ib/II study of APG-2575 as a single agent in patients with advanced solid tumors or in combination with anti-cancer agents such as CDK 4/6 inhibitor palbociclib in patients with ER+/HER2- metastatic breast cancer (mBC) who have progressed or relapsed after first line therapy
Description
The phase Ⅰb is dose escalation of APG-2575 as a single agent or in combination with palbociclib. A standard 3+3 design will be used to determine the MTD of APG-2575 as single agent in patients with solid tumors and MTD and RP2D of APG-2575 in combination with palbociclib in patients with breast cancer (MTD-combo). The phase II portion is a signal seeking expansion of APG-2575 at RP2D in combination with palbociclib in patients with ER+/HER2- metastatic breast cancers who have progressed during or relapsed after CDK 4/6inhibitor therapy. The phase Ⅱ portion will be conducted based on Simon's Minimax two stage design.
Eligibility
Inclusion Criteria:
Age ≥ 18 years. 2. Histologically or cytologically confirmed solid tumors; These locally
advanced or metastatic diseases have no standard effective therapy available as judged by
the investigator. 3. For the patients with breast cancer:
1. Must have histological or cytological confirmation of metastatic carcinoma of the
breast (either from the primary or metastatic site), with the following tumor
molecular characteristics (as determined from pre-screening testing):
1. ER positive.
2. HER2 negative - non-amplified (per ASCO/CAP guidelines).
2. Must have been treated with CDK4/6 inhibitor in the metastatic setting. And the
patients must have experienced disease progression during or recurrence after CDK4/6
inhibitor therapy, which must have been administered for a minimum of 8 weeks prior to
progression.
3. Must have measurable disease (according to RECIST v1.1) or evaluable disease. Boneonly
metastases are allowed.
4. Physiological postmenopausal, defined as:
1. Age ≥60 years, or
2. Age <60 years and undergone bilateral oophorectomy or medically confirmed ovarian
failure, or
3. Age <60 years and have cessation of regular menses for at least 12 consecutive
months with no alternative pathological or physiological cause and have serum
levels of estradiol and FSH within the reference range for postmenopausal
females.
4. Premenopausal treated with LHRH analogues APG2575XU103 Version 1.0. / March 8,
2021 APG-2575 Ascentage Pharma Group Inc. Confidential Page 51 of 108 4. ECOG ≤
1. 5. Adequate organ and bone marrow function within 14 days prior to
registration:
1) Hemoglobin ≥ 90 g/L. 2) Absolute neutrophil count ≥ 1.5 x 109
- L. Note: Use of growth-factors to maintain ANC criterion is not permitted 3) Platelet
count ≥ 100 x 109
- L. Note: Use of transfusions or thrombopoietic agents to achieve baseline platelet
count criterion is prohibited. 4) ALT and AST ≤ 3 x upper limit of normal (ULN), or ≤
5 x ULN if liver metastases are present. 5) Total serum bilirubin ≤ 1.5 x ULN.
Patient's with Gilbert's syndrome may have a total serum bilirubin > 1.5 x ULN. 6)
Serum creatinine ≤ 1.5 x upper limit of normal (ULN); if serum creatinine is >1.5 X
ULN, creatinine clearance must be ≥ 50 mL/min (Cockcroft-Gault). 6. Female patients
with childbearing potential must have negative urine or serum pregnancy test within 14
days prior to registration. 7. Able to swallow whole tablets. 8. Willingness to use
contraception that is deemed effective for the patients with child bearing potential
(postmenopausal women must have been amenorrhea for at least 12 months to be
considered of non-childbearing potential) and their partners throughout the treatment
period and for at least three months following the last dose of study drug.
9. Brain metastases with clinically controlled neurologic symptoms. 10. Able to sign
written informed consent with willingness and ability to comply with study procedures
and follow-up examination. 11. Patient assigned to combination therapy, must provide
sufficient archival tumor lesion or willing to provide fresh biopsy if no archival
tissue available and core or excisional biopsy of a tumor lesion where feasible.
Patients cannot provide a fresh biopsy (e.g. inaccessible or patient safety concern)
may be eligible upon agreement from the sponsor. -
Exclusion Criteria:
- Receive any anti-cancer therapy within 14 days prior to the first dose of study drug,
including chemotherapy, radiation therapy, surgery, targeted therapy, steroid therapy,
endocrine therapy or other investigational therapy with the exception of hormones for
hypothyroidism or estrogen replacement therapy (ERT) for non-breast cancer patients,
or has had tumor embolization. Patients must have a 5x half-lives wash out time period
or 14 for small molecules or 28 days for biologics including IO agents, gene or
cellular therapeutic agents, respectively.
These following therapies are permitted:
a. Bisphosphonate or denosumab therapy for patients with bone metastases. APG2575XU103
Version 1.0. / March 8, 2021 APG-2575 Ascentage Pharma Group Inc. Confidential Page 52 of
108 b. Ovarian suppression in pre- and peri-menopausal patients. c. Palliative
radiotherapy. 2. Receive any following agents within 14 days prior to the first dose of
study drugs:
1. Strong CYP3A inhibitors or inducers
2. Drugs that are known to prolong the QT interval. 3. Continuance of toxicities due to
prior radiotherapy or chemotherapy agents that do not recover to < Grade 2, exception
being clinically insignificant toxicities of prior chemo/radiation such as
lymphocytopenia or electrolyte abnormalities. 4. Pregnant or lactating. 5. Have a
major surgery within 28 days from study entry, or have had minor surgery within 7 days
of study entry. 6. Active symptomatic pathogenic infection including fungal, bacterial
and/or viral infection including, but not limited to, active human immunodeficiency
virus (HIV) or viral hepatitis (B or C) or active COVID-19. (Patients that have
received a COVID-19 vaccination will be considered as eligible for the study.) 7.
Unstable angina, myocardial infarction, or a coronary revascularization procedure
within 180 days of study entry. Patients with a QTc ≥ 480 msec (based on the mean
value of the triplicate ECGs), family or personal history of long or short QT
syndrome, Brugada syndrome or known history of QTc prolongation, or Torsade de Pointes
8. Prior use of a Bcl-2 inhibitor. 9. Any other condition or circumstance that would,
in the opinion of the investigator, make the patient unsuitable for participation in
the study. -