A Phase Ib Safety lead-in, Followed by Phase II Trial of ADG106 in Combination With Neoadjuvant Doxorubicin and Cyclophosphamide Followed by Paclitaxel in Stage I-III HER2 Negative Breast Cancer
Overview
- Phase
- Phase 1
- Status
- Active, not recruiting
- Enrollment
- 66
- Locations
- 1
- Primary Endpoint
- Number of participant with treatment related toxicities
Overview
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
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Sequential
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to 99 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Patients may be included in the study only if they meet all of the following criteria:
- •All patients must sign an informed consent in accordance with local institutional guidelines.
- •18 years and above of age.
- •Estimated life expectancy of at least 12 weeks.
- •Has recovered from acute toxicities from prior anti-cancer therapies (phase Ib).
- •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.
- •Measurable disease by RECIST 1.1 criteria.
- •Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-
Exclusion Criteria
- •Patients will be excluded from the study for any of the following reasons:
- •Treatment within the last 30 days with any investigational drug.
- •Concurrent administration of any other tumor therapy, including cytotoxic chemotherapy, hormonal therapy, and immunotherapy.
- •Major surgery within 28 days of study drug administration.
- •Active infection that in the opinion of the investigator would compromise the patient's ability to tolerate therapy.
- •Serious concomitant disorders that would compromise the safety of the patient or compromise the patient's ability to complete the study, at the discretion of the investigator.
- •Active, known or suspected autoimmune disease. Subjects with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enrol.
- •Subjects with a condition requiring systemic treatment with either corticosteroids (\>10mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of randomization. Inhaled or topical steroids, and adrenal replacement steroid \>10mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
- •Subjects with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity.
- •Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
Arms & Interventions
ADG106 combined with dose dense Doxorubicin and Cyclophosphamide (Phase Ib)
Intravenous ADG106 + 2 weekly doxorubicin and cyclophosphamide
Intervention: ADG106 (Drug)
ADG106 combined with dose dense Doxorubicin and Cyclophosphamide (Phase Ib)
Intravenous ADG106 + 2 weekly doxorubicin and cyclophosphamide
Intervention: Doxorubicin (Drug)
ADG106 combined with dose dense Doxorubicin and Cyclophosphamide (Phase Ib)
Intravenous ADG106 + 2 weekly doxorubicin and cyclophosphamide
Intervention: Cyclophosphamide (Drug)
ADG106 combined with Paclitaxel (Phase Ib)
Intravenous ADG106 + weekly paclitaxel
Intervention: ADG106 (Drug)
ADG106 combined with Paclitaxel (Phase Ib)
Intravenous ADG106 + weekly paclitaxel
Intervention: Paclitaxel (Drug)
ADG106 combined with dose dense Doxorubicin and Cyclophosphamide follow by Paclitaxel (Phase II)
Intravenous ADG106 combined with two weekly doxorubicin and cyclophosphamide followed intravenous ADG106 combined with weekly paclitaxel
Intervention: ADG106 (Drug)
ADG106 combined with dose dense Doxorubicin and Cyclophosphamide follow by Paclitaxel (Phase II)
Intravenous ADG106 combined with two weekly doxorubicin and cyclophosphamide followed intravenous ADG106 combined with weekly paclitaxel
Intervention: Doxorubicin (Drug)
ADG106 combined with dose dense Doxorubicin and Cyclophosphamide follow by Paclitaxel (Phase II)
Intravenous ADG106 combined with two weekly doxorubicin and cyclophosphamide followed intravenous ADG106 combined with weekly paclitaxel
Intervention: Cyclophosphamide (Drug)
ADG106 combined with dose dense Doxorubicin and Cyclophosphamide follow by Paclitaxel (Phase II)
Intravenous ADG106 combined with two weekly doxorubicin and cyclophosphamide followed intravenous ADG106 combined with weekly paclitaxel
Intervention: Paclitaxel (Drug)
Outcomes
Primary Outcomes
Number of participant with treatment related toxicities
Time Frame: 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
Time Frame: After 20 weeks of neoadjuvant chemotherapy
Biological changes on immunohistochemistry will be evaluated using paraffin-embedded tumor specimens.
Secondary Outcomes
- 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))
- Overall survival in Phase Ib(From enrolment till date of death or final follow up visit (maximum 1 year after last treatment dose))
- 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)
- 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).)
- Clinical response rate in Phase II(baseline, at the end of 2 weeks, 4 weeks, 8 weeks, 10 weeks, 12 weeks of treatment.)
- Pathological complete response rate in Phase II(after 20 weeks neoadjuvant chemotherapy)
- Relapse free survival in Phase II(From enrolment to final follow up visit (maximum 6 years from last treatment dose))