Advanced Solid Tumor, HER2-negative Breast Cancer
Conditions
Keywords
HER2-negative Breast Cancer, ADG106, neoadjuvant doxorubicin and cyclophosphamide, paclitaxel
Brief summary
This is an open label, lead in phase Ib dose confirmation study in patients with advanced solid tumors, followed by a phase II single arm study as neoadjuvant therapy in stage I-III HER2 negative breast cancer. Primary Objectives * To determine the safety profile of combination of ADG106 with dose dense doxorubicin/cyclophosphamide, and with weekly paclitaxel. * To determine the Recommended Phase 2 Dose (RP2D) of ADG106 in combination with dose dense doxorubicin/cyclophosphamide, and with weekly paclitaxel. * To evaluate biological changes on immunohistochemistry in HER2 negative breast cancer after treatment with ADG106 alone and in combination with chemotherapy. Secondary Objectives * To determine the efficacy of combination of ADG106 with standard neoadjuvant combination chemotherapy in HER2 negative breast cancer: objective response rates. * To correlate tumor and plasma biomarkers with efficacy outcomes.
Detailed description
The phase Ib segment will be carried out with a standard 3+3 dose de-escalation design. Patients with advanced/ metastatic solid organ cancers will be enrolled in 2 parallel cohorts. Cohort 1 will receive ADG106 in combination with dose dense doxorubicin/ cyclophosphamide (AC). Cohort 2 will receive ADG106 in combination with weekly paclitaxel. In the phase II portion, patients with stage I-III HER2 negative breast cancer planned for neoadjuvant chemotherapy will be enrolled. Patients will be treated with neoadjuvant chemotherapy (ddAC followed by paclitaxel for 12 weeks) combined with ADG106, before definitive breast cancer surgery
Interventions
DRUGADG106
Administered as an intravenous infusion over 60-90 minutes in the initial cycle and over 30 minutes in subsequent cycle if well tolerated.
DRUGDoxorubicin
Administered as an intravenous infusion.
DRUGCyclophosphamide
Administered as an intravenous infusion.
DRUGPaclitaxel
Administered as an intravenous infusion.
Sponsors
Adagene Inc
National University Hospital, Singapore
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Phase Ib: A 3+3 dose escalation design will be used to determine the RP2D dose of ADG106 in combination with ddAC and paclitaxel respectively. Phase II: ADG106 will be combined with ddAC followed by paclitaxel as neoadjuvant chemotherapy in patients with stage I-III HER2 negative breast cancer.
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
Patients may be included in the study only if they meet all of the following criteria: 1. All patients must sign an informed consent in accordance with local institutional guidelines. 2. 18 years and above of age. 3. Estimated life expectancy of at least 12 weeks. 4. Has recovered from acute toxicities from prior anti-cancer therapies (phase Ib). 5. a) Phase Ib: Patients with histologically or cytologically confirmed advanced or metastatic solid tumors who have radiological evidence of progressive disease on study entry that are deemed likely to benefit from either dose dense doxorubicin/ cyclophosphamide or weekly paclitaxel. * There is no upper limit on the number of prior treatments provided all inclusion/
Exclusion criteria
are met. Hormone ablation therapy is considered an anti-cancer regimen. Radiation therapy and surgery are not considered anti-cancer regimens. * Prior receipt of immunotherapy is allowed. b) Phase II: Untreated stage I-III HER2 negative breast cancer patients who are planned for neoadjuvant chemotherapy followed by definitive breast cancer surgery. 6. Measurable disease by RECIST 1.1 criteria. 7. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1. 8. Left ventricular ejection fraction of ≥ 50% for Cohort 1 in phase Ib and all patients in phase II. 9. Adequate bone marrow function and organ function within 2 weeks of study treatment. 1. Adequate hematologic function defined as: * Absolute neutrophil count (ANC) ≥ 1.5 x 109/L * Platelets ≥ 100 x 109/L * Hemoglobin ≥ 9 x 109/L 2. Adequate hepatic function defined as: * Bilirubin \< 1.5 times the upper limit of normal (ULN) * ALT or AST \< 2.5 times ULN (or \< 5 times ULN with presence of liver metastases) 3. Adequate renal function defined as: \- Calculated creatinine clearance of ≥ 60 mL/min, calculated using the formula of Cockroft and Gault: (140-Age) x Mass (kg)/(72 x creatinine mg/dL); multiply by 0.85 if female. 4. Adequate coagulation function defined as: * Activated partial thromboplastin time (aPTT) ≤1.5 x ULN * International normalized ratio (INR) ≤1.5 x ULN (Exception: INR 2 to ≤3 x ULN is acceptable for patients on warfarin anticoagulation 10. Patients with reproductive potential must use an approved contraceptive method if appropriate (e.g., intrauterine device, birth control pills, or barrier device) during and for three months after the study. Females with childbearing potential must have a negative serum pregnancy test within 7 days prior to study enrolment. 11. Able to comply with study related procedures.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of participant with treatment related toxicities | From enrolment till 30 days after last dose of study treatment | Toxicities will be graded using the Common Terminology Criteria for Adverse Events (CTCAE) toxicity grading version 5.0. |
| Histological response after neoadjuvant ADG106 + chemotherapy | After 20 weeks of neoadjuvant chemotherapy | Biological changes on immunohistochemistry will be evaluated using paraffin-embedded tumor specimens. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Correlation of plasma biomarkers with efficacy outcome in Phase Ib | baseline, at the end of week 1, 2, 4, 6, 8, 10, 12, 14, 18, 30, 42, 54, 66 | Correlation of biomarkers with Objective Response Rate, Progression Free Survival, Overall Survival |
| Progression free survival in Phase Ib | From enrolment till disease progression or date of death or final follow-up visit (maximum 1 year after last treatment dose). | Defined as the time from the date of study enrolment to the first date of documented disease progression. |
| Objective response rate in Phase Ib | At the end of every 3 cycles up to 24 weeks, at the end of every 6 cycles after 24 weeks up to 60 weeks (each cycle is 2 weeks) | Complete and partial clinical response will be measured by RECIST 1.1. |
| Pathological complete response rate in Phase II | after 20 weeks neoadjuvant chemotherapy | Defined as any patient who demonstrates no histological evidence of invasive tumor in the primary breast site as well as in resected axillary lymph nodes. |
| Relapse free survival in Phase II | From enrolment to final follow up visit (maximum 6 years from last treatment dose) | Defined as the time from the date of study enrolment to the first date of documented disease relapse. |
| Clinical response rate in Phase II | baseline, at the end of 2 weeks, 4 weeks, 8 weeks, 10 weeks, 12 weeks of treatment. | Clinical response rate will be measured by calipers |
| Overall survival in Phase Ib | From enrolment till date of death or final follow up visit (maximum 1 year after last treatment dose) | Defined as the time from the date of study enrolment to the date of death from any cause, regardless of whether the death occurred during the study or following treatment discontinuation. |
Countries
Singapore
Outcome results
None listed