Clinical Trials List
Protocol NumberD967JC00002
2020-11-20 - 2025-12-31
Phase I
Recruiting7
ICD-10C50.911
Malignant neoplasm of unspecified site of right female breast
ICD-10C50.912
Malignant neoplasm of unspecified site of left female breast
ICD-10C50.919
Malignant neoplasm of unspecified site of unspecified female breast
ICD-10Z51.12
Encounter for antineoplastic immunotherapy
ICD-9174.9
Malignant neoplasm of female breast, unspecified
A Phase 1b Multicentre, Open-label, Modular, Dose-finding and Dose-expansion Study to Explore the Safety, Tolerability, Pharmacokinetics and Anti-tumour Activity of Trastuzumab Deruxtecan (T-DXd) in Combination with Other Anti-cancer Agents in Patients with Metastatic HER2-low Breast Cancer (DESTINY-Breast08)
-
Trial Applicant
PAREXEL INTERNATIONAL CO., LTD.
-
Sponsor
AstraZeneca
-
Trial scale
Multi-Regional Multi-Center
-
Update
2025/08/20
Investigators and Locations
Co-Principal Investigator
- Yi-Fang Tsai Division of General Surgery
- 賴亦貞 Division of Radiology
- Ta-Chung Chao Division of Radiation Therapy
- Jiun-I Lai Division of Radiation Therapy
- 林燕淑 Division of General Surgery
- 馮晉榮 Division of General Surgery
- 邱仁輝 Division of General Surgery
- Chun-Yu Liu Division of Hematology & Oncology
- Chi-Cheng Huang Division of General Surgery
The Actual Total Number of Participants Enrolled
0 Recruiting
Co-Principal Investigator
- Wen-Chi Shen Division of General Surgery
- Chan-Keng Yang Division of Hematology & Oncology
- Chi-Chang Yu Division of General Surgery
- 周旭桓 Division of General Surgery
- 沈士哲 Division of General Surgery
- Wen-Ling Kuo Division of General Surgery
- Yung-Chang Lin Division of Hematology & Oncology
- Mengting Peng Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Recruiting
Co-Principal Investigator
- KA-WAI TAM Division of General Surgery
- CHIH-MING SU 未分科
- Yao-Yu Hsieh Division of Hematology & Oncology
- CHIN-SHENG HUNG Division of General Surgery
- Tsu-Yi Chao Division of Hematology & Oncology
- 蘇智銘 Division of General Surgery
- Wei-Hong Cheng Division of Hematology & Oncology
- HUI-WEN LIU Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Recruiting
Co-Principal Investigator
- Meng-Jer Hsieh Division of Hematology & Oncology
- 裴松南 Division of Hematology & Oncology
- 李蕙鳴 Division of General Surgery
- 洪朝明 Division of General Surgery
- 蔡郁棻 Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Recruiting
The Actual Total Number of Participants Enrolled
0 Recruiting
Co-Principal Investigator
- 吳宜穎 Division of Hematology & Oncology
- 黃子權 Division of Hematology & Oncology
- 于承平 Division of Others
- 陳宇欽 Division of Hematology & Oncology
- 廖國秀 Division of General Surgery
- 張平穎 Division of Hematology & Oncology
- 葉人華 Division of Hematology & Oncology
- 何景良 Division of Hematology & Oncology
- 陳佳宏 Division of Hematology & Oncology
- 賴學緯 Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Recruiting
Co-Principal Investigator
- Liang-Chih Liu Division of General Surgery
- Yao-Chung Wu Division of General Surgery
- Chen-Teng Wu Division of General Surgery
- Chih-Jung Chen Division of General Surgery
The Actual Total Number of Participants Enrolled
0 Recruiting
Condition/Disease
Metastatic HER2-low Breast Cancer
Objectives
Primary:
To assess the safety and tolerability, and
determine the RP2D for novel combinations
of anti-cancer therapies with T-DXd
Secondary:
• To assess anti-tumour activity of novel
T-DXd combinations at the RP2D
• To assess the PK of T-DXd, total anti-HER2
antibody and MAAA-1181a in serum
• To assess the PK of durvalumab
• To investigate the immunogenicity of
T-DXd and durvalumab
Test Drug
Trastuzumab deruxtecan (ENHERTUR)
Durvalumab (Imfinzi?)
Capivasertib
Durvalumab (Imfinzi?)
Capivasertib
Active Ingredient
Trastuzumab deruxtecan (ENHERTUR)
Durvalumab (Imfinzi?)
Capivasertib
Durvalumab (Imfinzi?)
Capivasertib
Dosage Form
Injection
Dosage
4.4 ~ 5.4mg/kg IV
Endpoints
Primary:
• AEs, SAEs, DLTs, laboratory findings
Secondary:
• ORR defined as the proportion of patients who have
a confirmed CR or PR, as determined by the
investigator at local site per RECIST 1.1
• PFS defined as time from the date of first dose until
the date of progression as determined by the
investigator at local site per RECIST 1.1, or death
due to any cause
• OS defined as time from the date of first dose until
the date of death by any cause
• DoR defined as time from the date of first
documented response (which is subsequently
confirmed) until the date of documented
progression or death in the absence of disease
progression
• Serum concentration of T-DXd, total anti-HER2
antibody and MAAA-1181a
• Serum concentration of durvalumab
• Presence of ADAs for T-DXd and durvalumab
• AEs, SAEs, DLTs, laboratory findings
Secondary:
• ORR defined as the proportion of patients who have
a confirmed CR or PR, as determined by the
investigator at local site per RECIST 1.1
• PFS defined as time from the date of first dose until
the date of progression as determined by the
investigator at local site per RECIST 1.1, or death
due to any cause
• OS defined as time from the date of first dose until
the date of death by any cause
• DoR defined as time from the date of first
documented response (which is subsequently
confirmed) until the date of documented
progression or death in the absence of disease
progression
• Serum concentration of T-DXd, total anti-HER2
antibody and MAAA-1181a
• Serum concentration of durvalumab
• Presence of ADAs for T-DXd and durvalumab
Inclution Criteria
1. Capable of giving signed informed consent as described in Protocol Appendix A, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
2. Provision of signed and dated written Optional Genetic Research Information informed consent prior to collection of samples for optional genetic research that supports the AstraZeneca Genomics Initiative (Protocol Appendix D). (Not applicable in Taiwan)
Age
3. Patient must be ≥ 18 years of age at the time of signing the informed consent. (Participants in Taiwan must be at least 20 years of legal age)
Type of Patient and Disease Characteristics
4. Male or female patients who have pathologically documented breast cancer that:
Is advanced or metastatic;
Has a history of HER2-low expression, defined as IHC 2+/ISH- or IHC 1+ (ISH- or untested) with a validated assay. Where possible, assessment of HER2 status should be based on the most recent tumour biopsy sample.
Is documented as HR+ (either ER and/or PgR positive [ER or PgR ≥1%]) or ER and PgR negative (ER and PgR <1%) per ASCO/CAP guidelines. If a patient has had multiple ER/PgR results, the most recent test result will be used to confirm eligibility.
Was never previously diagnosed with HER2-positive (IHC 3+ or ISH+) disease as per ASCO/CAP guidelines.
5. Patients must have an adequate tumour tissue sample available (FFPE tissue block from the most recently collected pre-enrolment tumour sample [primary or recurrent cancer] is preferred). If it is not possible to provide a tissue block, a minimum of 20 freshly-cut unstained serial tumour slides are to be provided. A tumour specimen obtained from relapsed metastatic or locally advanced disease (if applicable) must also be submitted, if available and/or clinically feasible. Refer to the Pathology Lab Manual for further details.
6. ECOG PS of 0 or 1.
7. Radiological or objective evidence of disease progression on or after the last systemic therapy prior to starting study treatment.
8. Allowed/required prior lines of therapy are:
For patients with HR+ disease:
o Part 1: At least 1 prior treatment line of ET with or without a targeted therapy (such as CDK4/6, mTOR or PI3-K inhibitors), and at least 1 prior line of chemotherapy for MBC are required.
o Part 2: Only 1 prior treatment line of ET with or without a targeted therapy (such as CDK4/6, mTOR or PI3-K inhibitors) for MBC is allowed. No prior chemotherapy in the metastatic setting is allowed. Note there are no patients with HR+ disease in Part 2 of Modules 2 and 3.
For patients with HR- disease:
o Part 1: At least 1 prior line of chemotherapy for MBC is required. Note there are no patients with HR- disease in Part 1 of Modules 4 and 5.
o Part 2: For Module 2, no prior lines of therapy for MBC are allowed, and for Modules 1 and 3, only 1 prior line of chemotherapy for MBC is allowed. Note there are no patients with HR- disease in Part 2 of Modules 4 and 5.
9. LVEF ≥ 50% within 28 days before enrolment.
10. Adequate organ and bone marrow function within 14 days before treatment assignment as listed in Table 6.
Table 6 Laboratory Values for Adequate Organ and Bone Marrow Function
Item (Laboratory value)
Haemoglobin
≥ 9 g/dL (patients requiring ongoing transfusions or growth factor support to maintain haemoglobin ≥ 9 g/dL are not eligible. Red blood cell transfusion is not allowed within 1 week prior to screening assessment)
Absolute neutrophil count
≥ 1,500/mm3 (G-CSF administration is not allowed within 1 week prior to screening assessment)
Platelet count
≥ 100,000/mm3 (platelet transfusion is not allowed within 1 week prior to screening assessment)
Total bilirubin
≤ 1.5 × ULN if no liver metastases or < 3 × ULN in the presence of documented Gilbert’s Syndrome (unconjugated hyperbilirubinemia) or liver metastases at baseline
Alanine aminotransferase and aspartate aminotransferase
≤ 3 × ULN, < 5 ×ULN in patients with liver metastasis
Serum albumin
≥ 2.5 g/dL
Creatinine clearance
≥ 30 mL/min (as calculated using the Cockcroft and Gault equation) a
International normalised ratio/Prothrombin time and either partial thromboplastin time or activated partial thromboplastin time
≤ 1.5 × ULN
a CLcr (mL/min) = “[140 - age (years)] × weight (kg)" /"72 × serum creatinine (mg/dL)" {× 0.85 for females}
G-CSF = granulocyte colony stimulating factor; ULN = upper limit of normal
11. Minimum life expectancy of 12 weeks at screening.
12. At least 1 measurable lesion that is not previously irradiated and can be accurately assessed at baseline by CT or MRI and is suitable for repeated assessment as per RECIST 1.1 (see Protocol Appendix G). Tumour assessment by CT scan or MRI must be performed within 28 days prior to start of study treatment. For Part 1: Patients with non-measurable disease that can be assessed by CT scan or MRI or X-ray are also eligible.
13. Has adequate treatment washout period before enrolment, defined in Table 7.
Table 7 Adequate Treatment Washout Periods
Treatment(Washout period)
Major surgery
≥ 4 weeks
Radiation therapy
Including palliative stereotactic radiation therapy to chest: ≥ 4 weeks (palliative stereotactic radiation therapy to other areas: ≥ 2 weeks)
Any other systemic anti-cancer treatment such as chemotherapy, immunotherapy, immunosuppressive medication (other than corticosteroids) targeted therapy, retinoid therapy or hormonal therapy a
≥ 3 weeks (≥ 2 weeks or 5 half-lives, whichever is longer for small-molecule targeted agents or chemotherapy, such as 5-fluorouracil-based agents)
Antibody-based anti-cancer therapy
≥ 4 weeks, with the exception of RANKL inhibitors (eg, denosumab for the treatment of complications resulting from bone metastases)
Chloroquine/hydroxychloroquine
≥ 14 days
a Bisphosphonates are allowed
RANKL = Receptor activator of nuclear factor-kB (RANK), its ligand.
Reproduction
14. Evidence of postmenopausal status or negative serum pregnancy test for women of childbearing potential who are sexually active with a non-sterilised male partner.
For women of childbearing potential, a negative result for serum pregnancy test (test must have a sensitivity of at least 25 mIU/mL) must be available at the screening visit and urine beta-human chorionic gonadotropin pregnancy test prior to each administration of study treatment.
Women will be considered postmenopausal if they have been amenorrhoeic for 12 months without an alternative medical cause. The following age-specific requirements apply:
o Women aged ≥ 50 years will be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the postmenopausal range for the site.
o Women aged < 50 years will be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced oophorectomy with last menses >1 year ago, had chemotherapy-induced menopause with >1 year interval since last menses, or undergone surgical sterilisation (bilateral oophorectomy or hysterectomy).
15. Female patients of childbearing potential who are sexually active with a non-sterilised male partner must use at least one highly effective method of contraception (see Protocol Appendix H) from the time of screening and must agree to continue using such precautions for 7 months after the last dose of any study treatment. Not all methods of contraception are highly effective. The choice of contraception should be in line with international guidelines for advanced breast cancer. Current guidelines advise against the use of hormonal contraception in patients with breast cancer. Female patients must refrain from egg cell donation and breastfeeding while on study and for 7 months after the last dose of any study treatment. Not engaging in sexual activity for the duration of the study and drug washout period is an acceptable practice; however, periodic or occasional abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception.
16. Non-sterilised male patients who are sexually active with a female partner of childbearing potential must use a condom with spermicide from screening to 4 months after the final dose of study treatment. Not engaging in sexual activity for the duration of the study and drug washout period is an acceptable practice; however, periodic or occasional abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception. It is strongly recommended for the female partners male patients to also use at least one highly effective method of contraception throughout this period (see Protocol Appendix H). In addition, male patients should refrain from fathering a child or donating sperm during the study and for 4 months after the last dose of any study treatment.
17. Female patients must not donate, or retrieve for their own use, ova from the time of Screening and throughout the study treatment period, and for at least 7 months after the final study drug administration.
2. Provision of signed and dated written Optional Genetic Research Information informed consent prior to collection of samples for optional genetic research that supports the AstraZeneca Genomics Initiative (Protocol Appendix D). (Not applicable in Taiwan)
Age
3. Patient must be ≥ 18 years of age at the time of signing the informed consent. (Participants in Taiwan must be at least 20 years of legal age)
Type of Patient and Disease Characteristics
4. Male or female patients who have pathologically documented breast cancer that:
Is advanced or metastatic;
Has a history of HER2-low expression, defined as IHC 2+/ISH- or IHC 1+ (ISH- or untested) with a validated assay. Where possible, assessment of HER2 status should be based on the most recent tumour biopsy sample.
Is documented as HR+ (either ER and/or PgR positive [ER or PgR ≥1%]) or ER and PgR negative (ER and PgR <1%) per ASCO/CAP guidelines. If a patient has had multiple ER/PgR results, the most recent test result will be used to confirm eligibility.
Was never previously diagnosed with HER2-positive (IHC 3+ or ISH+) disease as per ASCO/CAP guidelines.
5. Patients must have an adequate tumour tissue sample available (FFPE tissue block from the most recently collected pre-enrolment tumour sample [primary or recurrent cancer] is preferred). If it is not possible to provide a tissue block, a minimum of 20 freshly-cut unstained serial tumour slides are to be provided. A tumour specimen obtained from relapsed metastatic or locally advanced disease (if applicable) must also be submitted, if available and/or clinically feasible. Refer to the Pathology Lab Manual for further details.
6. ECOG PS of 0 or 1.
7. Radiological or objective evidence of disease progression on or after the last systemic therapy prior to starting study treatment.
8. Allowed/required prior lines of therapy are:
For patients with HR+ disease:
o Part 1: At least 1 prior treatment line of ET with or without a targeted therapy (such as CDK4/6, mTOR or PI3-K inhibitors), and at least 1 prior line of chemotherapy for MBC are required.
o Part 2: Only 1 prior treatment line of ET with or without a targeted therapy (such as CDK4/6, mTOR or PI3-K inhibitors) for MBC is allowed. No prior chemotherapy in the metastatic setting is allowed. Note there are no patients with HR+ disease in Part 2 of Modules 2 and 3.
For patients with HR- disease:
o Part 1: At least 1 prior line of chemotherapy for MBC is required. Note there are no patients with HR- disease in Part 1 of Modules 4 and 5.
o Part 2: For Module 2, no prior lines of therapy for MBC are allowed, and for Modules 1 and 3, only 1 prior line of chemotherapy for MBC is allowed. Note there are no patients with HR- disease in Part 2 of Modules 4 and 5.
9. LVEF ≥ 50% within 28 days before enrolment.
10. Adequate organ and bone marrow function within 14 days before treatment assignment as listed in Table 6.
Table 6 Laboratory Values for Adequate Organ and Bone Marrow Function
Item (Laboratory value)
Haemoglobin
≥ 9 g/dL (patients requiring ongoing transfusions or growth factor support to maintain haemoglobin ≥ 9 g/dL are not eligible. Red blood cell transfusion is not allowed within 1 week prior to screening assessment)
Absolute neutrophil count
≥ 1,500/mm3 (G-CSF administration is not allowed within 1 week prior to screening assessment)
Platelet count
≥ 100,000/mm3 (platelet transfusion is not allowed within 1 week prior to screening assessment)
Total bilirubin
≤ 1.5 × ULN if no liver metastases or < 3 × ULN in the presence of documented Gilbert’s Syndrome (unconjugated hyperbilirubinemia) or liver metastases at baseline
Alanine aminotransferase and aspartate aminotransferase
≤ 3 × ULN, < 5 ×ULN in patients with liver metastasis
Serum albumin
≥ 2.5 g/dL
Creatinine clearance
≥ 30 mL/min (as calculated using the Cockcroft and Gault equation) a
International normalised ratio/Prothrombin time and either partial thromboplastin time or activated partial thromboplastin time
≤ 1.5 × ULN
a CLcr (mL/min) = “[140 - age (years)] × weight (kg)" /"72 × serum creatinine (mg/dL)" {× 0.85 for females}
G-CSF = granulocyte colony stimulating factor; ULN = upper limit of normal
11. Minimum life expectancy of 12 weeks at screening.
12. At least 1 measurable lesion that is not previously irradiated and can be accurately assessed at baseline by CT or MRI and is suitable for repeated assessment as per RECIST 1.1 (see Protocol Appendix G). Tumour assessment by CT scan or MRI must be performed within 28 days prior to start of study treatment. For Part 1: Patients with non-measurable disease that can be assessed by CT scan or MRI or X-ray are also eligible.
13. Has adequate treatment washout period before enrolment, defined in Table 7.
Table 7 Adequate Treatment Washout Periods
Treatment(Washout period)
Major surgery
≥ 4 weeks
Radiation therapy
Including palliative stereotactic radiation therapy to chest: ≥ 4 weeks (palliative stereotactic radiation therapy to other areas: ≥ 2 weeks)
Any other systemic anti-cancer treatment such as chemotherapy, immunotherapy, immunosuppressive medication (other than corticosteroids) targeted therapy, retinoid therapy or hormonal therapy a
≥ 3 weeks (≥ 2 weeks or 5 half-lives, whichever is longer for small-molecule targeted agents or chemotherapy, such as 5-fluorouracil-based agents)
Antibody-based anti-cancer therapy
≥ 4 weeks, with the exception of RANKL inhibitors (eg, denosumab for the treatment of complications resulting from bone metastases)
Chloroquine/hydroxychloroquine
≥ 14 days
a Bisphosphonates are allowed
RANKL = Receptor activator of nuclear factor-kB (RANK), its ligand.
Reproduction
14. Evidence of postmenopausal status or negative serum pregnancy test for women of childbearing potential who are sexually active with a non-sterilised male partner.
For women of childbearing potential, a negative result for serum pregnancy test (test must have a sensitivity of at least 25 mIU/mL) must be available at the screening visit and urine beta-human chorionic gonadotropin pregnancy test prior to each administration of study treatment.
Women will be considered postmenopausal if they have been amenorrhoeic for 12 months without an alternative medical cause. The following age-specific requirements apply:
o Women aged ≥ 50 years will be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the postmenopausal range for the site.
o Women aged < 50 years will be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced oophorectomy with last menses >1 year ago, had chemotherapy-induced menopause with >1 year interval since last menses, or undergone surgical sterilisation (bilateral oophorectomy or hysterectomy).
15. Female patients of childbearing potential who are sexually active with a non-sterilised male partner must use at least one highly effective method of contraception (see Protocol Appendix H) from the time of screening and must agree to continue using such precautions for 7 months after the last dose of any study treatment. Not all methods of contraception are highly effective. The choice of contraception should be in line with international guidelines for advanced breast cancer. Current guidelines advise against the use of hormonal contraception in patients with breast cancer. Female patients must refrain from egg cell donation and breastfeeding while on study and for 7 months after the last dose of any study treatment. Not engaging in sexual activity for the duration of the study and drug washout period is an acceptable practice; however, periodic or occasional abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception.
16. Non-sterilised male patients who are sexually active with a female partner of childbearing potential must use a condom with spermicide from screening to 4 months after the final dose of study treatment. Not engaging in sexual activity for the duration of the study and drug washout period is an acceptable practice; however, periodic or occasional abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception. It is strongly recommended for the female partners male patients to also use at least one highly effective method of contraception throughout this period (see Protocol Appendix H). In addition, male patients should refrain from fathering a child or donating sperm during the study and for 4 months after the last dose of any study treatment.
17. Female patients must not donate, or retrieve for their own use, ova from the time of Screening and throughout the study treatment period, and for at least 7 months after the final study drug administration.
Exclusion Criteria
1. Capable of giving signed informed consent as described in Protocol Appendix A, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
2. Provision of signed and dated written Optional Genetic Research Information informed consent prior to collection of samples for optional genetic research that supports the AstraZeneca Genomics Initiative (Protocol Appendix D). (Not applicable in Taiwan)
Age
3. Patient must be ≥ 18 years of age at the time of signing the informed consent. (Participants in Taiwan must be at least 20 years of legal age)
Type of Patient and Disease Characteristics
4. Male or female patients who have pathologically documented breast cancer that:
Is advanced or metastatic;
Has a history of HER2-low expression, defined as IHC 2+/ISH- or IHC 1+ (ISH- or untested) with a validated assay. Where possible, assessment of HER2 status should be based on the most recent tumour biopsy sample.
Is documented as HR+ (either ER and/or PgR positive [ER or PgR ≥1%]) or ER and PgR negative (ER and PgR <1%) per ASCO/CAP guidelines. If a patient has had multiple ER/PgR results, the most recent test result will be used to confirm eligibility.
Was never previously diagnosed with HER2-positive (IHC 3+ or ISH+) disease as per ASCO/CAP guidelines.
5. Patients must have an adequate tumour tissue sample available (FFPE tissue block from the most recently collected pre-enrolment tumour sample [primary or recurrent cancer] is preferred). If it is not possible to provide a tissue block, a minimum of 20 freshly-cut unstained serial tumour slides are to be provided. A tumour specimen obtained from relapsed metastatic or locally advanced disease (if applicable) must also be submitted, if available and/or clinically feasible. Refer to the Pathology Lab Manual for further details.
6. ECOG PS of 0 or 1.
7. Radiological or objective evidence of disease progression on or after the last systemic therapy prior to starting study treatment.
8. Allowed/required prior lines of therapy are:
For patients with HR+ disease:
o Part 1: At least 1 prior treatment line of ET with or without a targeted therapy (such as CDK4/6, mTOR or PI3-K inhibitors), and at least 1 prior line of chemotherapy for MBC are required.
o Part 2: Only 1 prior treatment line of ET with or without a targeted therapy (such as CDK4/6, mTOR or PI3-K inhibitors) for MBC is allowed. No prior chemotherapy in the metastatic setting is allowed. Note there are no patients with HR+ disease in Part 2 of Modules 2 and 3.
For patients with HR- disease:
o Part 1: At least 1 prior line of chemotherapy for MBC is required. Note there are no patients with HR- disease in Part 1 of Modules 4 and 5.
o Part 2: For Module 2, no prior lines of therapy for MBC are allowed, and for Modules 1 and 3, only 1 prior line of chemotherapy for MBC is allowed. Note there are no patients with HR- disease in Part 2 of Modules 4 and 5.
9. LVEF ≥ 50% within 28 days before enrolment.
10. Adequate organ and bone marrow function within 14 days before treatment assignment as listed in Table 6.
Table 6 Laboratory Values for Adequate Organ and Bone Marrow Function
Item Laboratory value
Haemoglobin ≥ 9 g/dL (patients requiring ongoing transfusions or growth factor support to maintain haemoglobin ≥ 9 g/dL are not eligible. Red blood cell transfusion is not allowed within 1 week prior to screening assessment)
Absolute neutrophil count ≥ 1,500/mm3 (G-CSF administration is not allowed within 1 week prior to screening assessment)
Platelet count ≥ 100,000/mm3 (platelet transfusion is not allowed within 1 week prior to screening assessment)
Total bilirubin ≤ 1.5 × ULN if no liver metastases or < 3 × ULN in the presence of documented Gilbert’s Syndrome (unconjugated hyperbilirubinemia) or liver metastases at baseline
Alanine aminotransferase and aspartate aminotransferase ≤ 3 × ULN, < 5 ×ULN in patients with liver metastasis
Serum albumin ≥ 2.5 g/dL
Creatinine clearance ≥ 30 mL/min (as calculated using the Cockcroft and Gault equation) a
International normalised ratio/Prothrombin time and either partial thromboplastin time or activated partial thromboplastin time ≤ 1.5 × ULN
a CLcr (mL/min) = “[140 - age (years)] × weight (kg)" /"72 × serum creatinine (mg/dL)" {× 0.85 for females}
G-CSF = granulocyte colony stimulating factor; ULN = upper limit of normal
11. Minimum life expectancy of 12 weeks at screening.
12. At least 1 measurable lesion that is not previously irradiated and can be accurately assessed at baseline by CT or MRI and is suitable for repeated assessment as per RECIST 1.1 (see Protocol Appendix G). Tumour assessment by CT scan or MRI must be performed within 28 days prior to start of study treatment. For Part 1: Patients with non-measurable disease that can be assessed by CT scan or MRI or X-ray are also eligible.
13. Has adequate treatment washout period before enrolment, defined in Table 7.
Table 7 Adequate Treatment Washout Periods
Treatment Washout period
Major surgery ≥ 4 weeks
Radiation therapy Including palliative stereotactic radiation therapy to chest: ≥ 4 weeks (palliative stereotactic radiation therapy to other areas: ≥ 2 weeks)
Any other systemic anti-cancer treatment such as chemotherapy, immunotherapy, immunosuppressive medication (other than corticosteroids) targeted therapy, retinoid therapy or hormonal therapy a ≥ 3 weeks (≥ 2 weeks or 5 half-lives, whichever is longer for small-molecule targeted agents or chemotherapy, such as 5-fluorouracil-based agents)
Antibody-based anti-cancer therapy ≥ 4 weeks, with the exception of RANKL inhibitors (eg, denosumab for the treatment of complications resulting from bone metastases)
Chloroquine/hydroxychloroquine ≥ 14 days
a Bisphosphonates are allowed
RANKL = Receptor activator of nuclear factor-kB (RANK), its ligand.
Reproduction
14. Evidence of postmenopausal status or negative serum pregnancy test for women of childbearing potential who are sexually active with a non-sterilised male partner.
For women of childbearing potential, a negative result for serum pregnancy test (test must have a sensitivity of at least 25 mIU/mL) must be available at the screening visit and urine beta-human chorionic gonadotropin pregnancy test prior to each administration of study treatment.
Women will be considered postmenopausal if they have been amenorrhoeic for 12 months without an alternative medical cause. The following age-specific requirements apply:
o Women aged ≥ 50 years will be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the postmenopausal range for the site.
o Women aged < 50 years will be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced oophorectomy with last menses >1 year ago, had chemotherapy-induced menopause with >1 year interval since last menses, or undergone surgical sterilisation (bilateral oophorectomy or hysterectomy).
15. Female patients of childbearing potential who are sexually active with a non-sterilised male partner must use at least one highly effective method of contraception (see Protocol Appendix H) from the time of screening and must agree to continue using such precautions for 7 months after the last dose of any study treatment. Not all methods of contraception are highly effective. The choice of contraception should be in line with international guidelines for advanced breast cancer. Current guidelines advise against the use of hormonal contraception in patients with breast cancer. Female patients must refrain from egg cell donation and breastfeeding while on study and for 7 months after the last dose of any study treatment. Not engaging in sexual activity for the duration of the study and drug washout period is an acceptable practice; however, periodic or occasional abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception.
16. Non-sterilised male patients who are sexually active with a female partner of childbearing potential must use a condom with spermicide from screening to 4 months after the final dose of study treatment. Not engaging in sexual activity for the duration of the study and drug washout period is an acceptable practice; however, periodic or occasional abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception. It is strongly recommended for the female partners male patients to also use at least one highly effective method of contraception throughout this period (see Protocol Appendix H). In addition, male patients should refrain from fathering a child or donating sperm during the study and for 4 months after the last dose of any study treatment.
17. Female patients must not donate, or retrieve for their own use, ova from the time of Screening and throughout the study treatment period, and for at least 7 months after the final study drug administration.
2. Provision of signed and dated written Optional Genetic Research Information informed consent prior to collection of samples for optional genetic research that supports the AstraZeneca Genomics Initiative (Protocol Appendix D). (Not applicable in Taiwan)
Age
3. Patient must be ≥ 18 years of age at the time of signing the informed consent. (Participants in Taiwan must be at least 20 years of legal age)
Type of Patient and Disease Characteristics
4. Male or female patients who have pathologically documented breast cancer that:
Is advanced or metastatic;
Has a history of HER2-low expression, defined as IHC 2+/ISH- or IHC 1+ (ISH- or untested) with a validated assay. Where possible, assessment of HER2 status should be based on the most recent tumour biopsy sample.
Is documented as HR+ (either ER and/or PgR positive [ER or PgR ≥1%]) or ER and PgR negative (ER and PgR <1%) per ASCO/CAP guidelines. If a patient has had multiple ER/PgR results, the most recent test result will be used to confirm eligibility.
Was never previously diagnosed with HER2-positive (IHC 3+ or ISH+) disease as per ASCO/CAP guidelines.
5. Patients must have an adequate tumour tissue sample available (FFPE tissue block from the most recently collected pre-enrolment tumour sample [primary or recurrent cancer] is preferred). If it is not possible to provide a tissue block, a minimum of 20 freshly-cut unstained serial tumour slides are to be provided. A tumour specimen obtained from relapsed metastatic or locally advanced disease (if applicable) must also be submitted, if available and/or clinically feasible. Refer to the Pathology Lab Manual for further details.
6. ECOG PS of 0 or 1.
7. Radiological or objective evidence of disease progression on or after the last systemic therapy prior to starting study treatment.
8. Allowed/required prior lines of therapy are:
For patients with HR+ disease:
o Part 1: At least 1 prior treatment line of ET with or without a targeted therapy (such as CDK4/6, mTOR or PI3-K inhibitors), and at least 1 prior line of chemotherapy for MBC are required.
o Part 2: Only 1 prior treatment line of ET with or without a targeted therapy (such as CDK4/6, mTOR or PI3-K inhibitors) for MBC is allowed. No prior chemotherapy in the metastatic setting is allowed. Note there are no patients with HR+ disease in Part 2 of Modules 2 and 3.
For patients with HR- disease:
o Part 1: At least 1 prior line of chemotherapy for MBC is required. Note there are no patients with HR- disease in Part 1 of Modules 4 and 5.
o Part 2: For Module 2, no prior lines of therapy for MBC are allowed, and for Modules 1 and 3, only 1 prior line of chemotherapy for MBC is allowed. Note there are no patients with HR- disease in Part 2 of Modules 4 and 5.
9. LVEF ≥ 50% within 28 days before enrolment.
10. Adequate organ and bone marrow function within 14 days before treatment assignment as listed in Table 6.
Table 6 Laboratory Values for Adequate Organ and Bone Marrow Function
Item Laboratory value
Haemoglobin ≥ 9 g/dL (patients requiring ongoing transfusions or growth factor support to maintain haemoglobin ≥ 9 g/dL are not eligible. Red blood cell transfusion is not allowed within 1 week prior to screening assessment)
Absolute neutrophil count ≥ 1,500/mm3 (G-CSF administration is not allowed within 1 week prior to screening assessment)
Platelet count ≥ 100,000/mm3 (platelet transfusion is not allowed within 1 week prior to screening assessment)
Total bilirubin ≤ 1.5 × ULN if no liver metastases or < 3 × ULN in the presence of documented Gilbert’s Syndrome (unconjugated hyperbilirubinemia) or liver metastases at baseline
Alanine aminotransferase and aspartate aminotransferase ≤ 3 × ULN, < 5 ×ULN in patients with liver metastasis
Serum albumin ≥ 2.5 g/dL
Creatinine clearance ≥ 30 mL/min (as calculated using the Cockcroft and Gault equation) a
International normalised ratio/Prothrombin time and either partial thromboplastin time or activated partial thromboplastin time ≤ 1.5 × ULN
a CLcr (mL/min) = “[140 - age (years)] × weight (kg)" /"72 × serum creatinine (mg/dL)" {× 0.85 for females}
G-CSF = granulocyte colony stimulating factor; ULN = upper limit of normal
11. Minimum life expectancy of 12 weeks at screening.
12. At least 1 measurable lesion that is not previously irradiated and can be accurately assessed at baseline by CT or MRI and is suitable for repeated assessment as per RECIST 1.1 (see Protocol Appendix G). Tumour assessment by CT scan or MRI must be performed within 28 days prior to start of study treatment. For Part 1: Patients with non-measurable disease that can be assessed by CT scan or MRI or X-ray are also eligible.
13. Has adequate treatment washout period before enrolment, defined in Table 7.
Table 7 Adequate Treatment Washout Periods
Treatment Washout period
Major surgery ≥ 4 weeks
Radiation therapy Including palliative stereotactic radiation therapy to chest: ≥ 4 weeks (palliative stereotactic radiation therapy to other areas: ≥ 2 weeks)
Any other systemic anti-cancer treatment such as chemotherapy, immunotherapy, immunosuppressive medication (other than corticosteroids) targeted therapy, retinoid therapy or hormonal therapy a ≥ 3 weeks (≥ 2 weeks or 5 half-lives, whichever is longer for small-molecule targeted agents or chemotherapy, such as 5-fluorouracil-based agents)
Antibody-based anti-cancer therapy ≥ 4 weeks, with the exception of RANKL inhibitors (eg, denosumab for the treatment of complications resulting from bone metastases)
Chloroquine/hydroxychloroquine ≥ 14 days
a Bisphosphonates are allowed
RANKL = Receptor activator of nuclear factor-kB (RANK), its ligand.
Reproduction
14. Evidence of postmenopausal status or negative serum pregnancy test for women of childbearing potential who are sexually active with a non-sterilised male partner.
For women of childbearing potential, a negative result for serum pregnancy test (test must have a sensitivity of at least 25 mIU/mL) must be available at the screening visit and urine beta-human chorionic gonadotropin pregnancy test prior to each administration of study treatment.
Women will be considered postmenopausal if they have been amenorrhoeic for 12 months without an alternative medical cause. The following age-specific requirements apply:
o Women aged ≥ 50 years will be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the postmenopausal range for the site.
o Women aged < 50 years will be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced oophorectomy with last menses >1 year ago, had chemotherapy-induced menopause with >1 year interval since last menses, or undergone surgical sterilisation (bilateral oophorectomy or hysterectomy).
15. Female patients of childbearing potential who are sexually active with a non-sterilised male partner must use at least one highly effective method of contraception (see Protocol Appendix H) from the time of screening and must agree to continue using such precautions for 7 months after the last dose of any study treatment. Not all methods of contraception are highly effective. The choice of contraception should be in line with international guidelines for advanced breast cancer. Current guidelines advise against the use of hormonal contraception in patients with breast cancer. Female patients must refrain from egg cell donation and breastfeeding while on study and for 7 months after the last dose of any study treatment. Not engaging in sexual activity for the duration of the study and drug washout period is an acceptable practice; however, periodic or occasional abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception.
16. Non-sterilised male patients who are sexually active with a female partner of childbearing potential must use a condom with spermicide from screening to 4 months after the final dose of study treatment. Not engaging in sexual activity for the duration of the study and drug washout period is an acceptable practice; however, periodic or occasional abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception. It is strongly recommended for the female partners male patients to also use at least one highly effective method of contraception throughout this period (see Protocol Appendix H). In addition, male patients should refrain from fathering a child or donating sperm during the study and for 4 months after the last dose of any study treatment.
17. Female patients must not donate, or retrieve for their own use, ova from the time of Screening and throughout the study treatment period, and for at least 7 months after the final study drug administration.
The Estimated Number of Participants
-
Taiwan
30 participants
-
Global
200 participants
