Intratumoral INT230-6 Followed by Neoadjuvant Immuno-chemotherapy in Patients With Early Triple-negative Breast Cancer (TNBC). An Open-label Randomized Two-cohort Phase 2 Clinical Trial. INVINCIBLE-4-SAKK
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 61
- 试验地点
- 19
- 主要终点
- Pathological complete response (pCR) in the primary tumor (ypT0/Tis) and affected lymph nodes (ypN0).
研究概览
简要总结
About 10-20% of all individuals with breast cancer have a so-called triple-negative tumor (TNBC). This type of breast cancer has a particularly unfavorable course and a higher mortality rate compared to other forms of breast cancer. Research studies show that it is important for individuals with TNBC to achieve a so-called pathologic complete response (pCR) to treatment. In the phase II study SAKK 66/22, it is being investigated whether the administration of the drug INT230-6 before surgery for breast cancer can increase the rate of pCR in the tumor and affected lymph nodes. The tolerability of INT230-6 as well as other factors such as response to treatment and the possibility of breast-conserving surgery are also being examined.
详细描述
Triple-negative breast cancer (TNBC) poses significant challenges due to its aggressiveness, high relapse rates, and increased mortality. The Keynote-522 study revealed a 19.6% incidence of event-free survival (EFS) events in early-stage TNBC patients over 39 months. Achieving pathological complete response (pCR) and clearing positive lymph nodes are crucial prognostic factors.
The IMP INT230-6 is a combination of the chemotherapeutic agents cisplatin and vinblastine, along with a molecule that facilitates their distribution in tumor tissue. INT230-6, currently in clinical trials, has demonstrated the ability to induce up to 95% necrosis in T2 breast cancer tumors and it has been observed to stimulate systemic immune activation during the period between diagnosis and surgery. Moreover, promising results have been seen in seven refractory breast cancer patients, resulting in decreased Ki67 levels and a median overall survival of 12 months.
Completed and ongoing U.S. clinical trials including 91 patient a window-of-opportunity trial demonstrate the safety and early activity of INT230-6, both alone and with checkpoint inhibitors like pembrolizumab and ipilimumab, particularly in resistant cases.
Based on the positive outcomes, it will be assessed within this clinical trial the safety and early clinical activity of INT230-6 in early TNBC patients, addressing the high unmet medical need in this challenging subtype.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Written informed consent according to country specific law and ICH GCP E6(R2) regulations before registration and prior to any trial specific procedures.
- •Newly histologically diagnosed, previously untreated locally advanced non-metastatic TNBC as defined by the most recent American Society of Clinical Oncology (ASCO) / College of American Pathologist (CAP) guidelines .
- •The following stages according to staging per American Joint Committee on Cancer (AJCC) for breast cancer staging criteria version 8 are included: cT1c (1.5-2cm) N1-3 M0 or cT2-4c N0-3 M
- •Multifocal and multicentric primary tumors are allowed and the tumor with the most advanced T stage should be used to assess eligibility. If multifocal or multicentric disease TNBC needs to be confirmed for each focus.
- •Measurable disease in the breast with at least one lesion with a diameter ≥ 1.5cm that is evaluable per RECIST v1.1, visible in ultrasound and injectable.
- •Male or female subject Age ≥ 18 years.
- •ECOG performance status 0-1
- •Adequate bone marrow function (administration of G-CSF, EPO and/or blood transfusion within 14 days before registration is not allowed):
- •neutrophil count ≥ 1.5 x 109/L
- •platelet count ≥ 100 x 109/L
- •hemoglobin ≥ 90 g/L
- •Adequate hepatic function:
- •total bilirubin ≤ 1.5 x ULN, or direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 x ULN
- •AST and ALT ≤ 2.5 x ULN,
- •Albumin 30 ≥ g/L
- •Lactate Dehydrogenase (LDH) <2.5 ULN
- •Adequate renal function: estimated glomerular filtration rate (eGFR) ≥ 50 ml/min/1.73 m2 (according to CKD-EPI formula)
- •Adequate cardiac function: Left ventricular Ejection Fraction (LVEF) ≥ 50% as determined by echocardiography (ECHO)
- •Adequate coagulation function:
- •INR ≤ 1.5 x ULN unless the patient is receiving anticoagulant therapy
- •aPTT ≤ 1.5 x ULN unless the patient is receiving anticoagulant therapy
- •If the patient is receiving anticoagulant therapy, the treating physician must determine that the anticoagulation can be stopped at least 24 hours prior to injection.
- •Women of childbearing potential must use highly effective contraception, are not pregnant or lactating and agree not to become pregnant during trial treatment and until 7 months after the last dose of INT230-6 or 6 months after standard of care treatment. A negative pregnancy test before inclusion into the trial is required for all women of childbearing potential. (www.swissmedicinfo.ch).
- •Men agree not to donate sperm or to father a child by using effective contraception during trial treatment and until 6 months after the last dose of INT230-6 or standard of care treatment (www.swissmedicinfo.ch).
排除标准
- •Inflammatory Breast Cancer cT4d
- •Unfavorable relation between tumor size and breast size as determined by judgement of the treating physician, surgeon and/or investigator, where tumor shrinkage during neoadjuvant immunochemotherapy is required for breast conserving surgery to be considered.
- •Unfavorable tumor location that can potentially result in an unfavorable cosmetic outcome (e.g. high upper inner quadrant) and/or close skin contact by judgment of the treating physician, surgeon and/or investigator.
- •The following histological subtypes of TNBC are excluded: Classic adenoid cystic carcinoma, secretory carcinoma, low-grade adenosquamous carcinoma, tall cell carcinoma with reversed polarity, high-grade metaplastic
- •History of invasive malignancy ≤3 years prior to signing informed consent (except treated basal cell or squamous cell skin cancer or in situ cervical cancer)
- •Prior chemotherapy, targeted therapy, radiation therapy or anti-PD-L1 agent for previous breast cancer or Ductal Carcinoma in Situ (DCIS) on the same side.
- •Concurrent bilateral breast cancer
- •Concomitant treatment with any other experimental drug for recent breast cancer diagnosis in another clinical trial.
- •Severe or uncontrolled cardiovascular disease (congestive heart failure NYHA II or IV; unstable angina pectoris, history of myocardial infarction and acute coronary syndrome requiring stenting/bypass surgery within the last six months, serious arrhythmias requiring medication (with exception of atrial fibrillation or paroxysmal supraventricular tachycardia), significant QT-prolongation, uncontrolled hypertension.
- •Known history of human immunodeficiency virus (HIV) or active chronic hepatitis C or hepatitis B virus infection or any uncontrolled active systemic infection requiring intravenous (iv) antimicrobial treatment.
- •Active autoimmune disease that required systemic treatment in past 2 years (e.g., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroid hormone replacement, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment.
- •History of (non-infectious) pneumonitis that required steroids or current pneumonitis.
- •Known history of tuberculosis.
- •Known history of allogeneic organ or stem cell transplant.
- •Receipt of live attenuated vaccine (including yellow fever vaccine) within 30 days prior to registration.
- •Diagnosis of immunodeficiency, concomitant or prior use of immunosuppressive medication within 7 days before registration, with the exceptions of local (intranasal, topical and inhaled) corticosteroids, or systemic corticosteroids which must not exceed 10 mg/day of prednisone or a dose equivalent corticosteroid, and the premedication for chemotherapy.
- •Concomitant anticoagulation with warfarin or equivalent vitamin K antagonists (e.g. phenprocoumon), factor Xa inhibitors (e.g. rivaroxaban, apixaban), direct thrombin inhibitors (e.g. dabigatran) or platelet inhibitors/antiplatelet agents that cannot be stopped 24 hours before the administration of INT230-
- •Aspirin (up to 300 mg/day) is allowed.
- •Any concomitant drugs contraindicated for use with the trial drug according to the Investigator Brochure (IB) and the immuno-chemotherapy treatment according to the approved product information.
- •Known hypersensitivity to trial drug or to any component of the trial drug or immuno-chemotherapy treatment.
- •Incapacitated adults and any other serious underlying medical, psychiatric, psychological, familial or geographical condition, which in the judgment of the investigator may interfere with the planned staging, treatment and follow-up, affect patient compliance or place the patient at high risk from treatment-related complications.
研究组 & 干预措施
Cohort A experimental
Intervention 1 week:
- 1 Injection of INT230-6 into primary tumor of the breast
Thereafter
- Standard of Care including surgery (30 weeks)
- Immuno-chemotherapy -> 24 weeks
Neoadjuvant therapy as Keynote-522 (Standard of Care) - 24 Weeks
Pembrolizumab q3W in combination with
- Cycles 1-4: Paclitaxel q1W + Carboplatin q1W or q3W
- Cycle 5-8: Doxorubicin or Epirubicin q3W + Cyclophospahmide q3W
- MRI
- Surgery
干预措施: INT230-6 (Drug)
Cohort A experimental
Intervention 1 week:
- 1 Injection of INT230-6 into primary tumor of the breast
Thereafter
- Standard of Care including surgery (30 weeks)
- Immuno-chemotherapy -> 24 weeks
Neoadjuvant therapy as Keynote-522 (Standard of Care) - 24 Weeks
Pembrolizumab q3W in combination with
- Cycles 1-4: Paclitaxel q1W + Carboplatin q1W or q3W
- Cycle 5-8: Doxorubicin or Epirubicin q3W + Cyclophospahmide q3W
- MRI
- Surgery
干预措施: neoadjuvant immuno-chemotherapy (Other)
Cohort B Standard of Care
Intervention 1 week:
- No intervention - start of immune-chemotherapy after randomization
Thereafter
- Standard of Care including surgery (30 weeks)
- Immuno-chemotherapy -> 24 weeks
Neoadjuvant therapy as Keynote-522 (Standard of Care) - 24 Weeks
Pembrolizumab q3W in combination with
- Cycles 1-4: Paclitaxel q1W + Carboplatin q1W or q3W
- Cycle 5-8: Doxorubicin or Epirubicin q3W + Cyclophospahmide q3W
- MRI
- Surgery
干预措施: neoadjuvant immuno-chemotherapy (Other)
结局指标
主要结局
Pathological complete response (pCR) in the primary tumor (ypT0/Tis) and affected lymph nodes (ypN0).
时间窗: At the date of tumor assessment after surgery, estimated at 29 to 32 weeks after treatment start for cohort A and at 27 to 30 weeks after treatment start for cohort B.
The two following criteria need to be fulfilled for pCR: No invasive breast cancer in primary tumor (noninvasive breast residuals allowed) ypT0/Tis No invasive breast cancer in affected lymph nodes ypN0 The primary endpoint will be analyzed based on the resected patients set. The endpoint is evaluated according to the assessment of the local pathologist.
次要结局
- pCR in lymph nodes(At the date of tumor assessment after surgery, estimated at 29 to 32 weeks after treatment start for cohort A and at 27 to 30 weeks after treatment start for cohort B.)
- pCR (invasive and in-situ, only invasive, respectively) in the breast(At the date of tumor assessment after surgery, estimated at 29 to 32 weeks after treatment start for cohort A and at 27 to 30 weeks after treatment start for cohort B.)
- Overall response according to RECIST v1.1(At 1 to 4 weeks after last SOC treatment and before surgery, estimated at 27 to 30 weeks after treatment start for cohort A and at 25 to 28 weeks after treatment start for cohort B.)
- Event free survival (EFS)(): From the date of randomization until the date of the event of interest up to 3 years after surgery.)
- Pattern of non pCR(At the date of tumor assessment after surgery, estimated at 29 to 32 weeks after treatment start for cohort A and at 27 to 30 weeks after treatment start for cohort B.)
- Radiological tumor response using two perpendicular diameters(At 1 to 4 weeks after last SOC treatment and before surgery, estimated at 27 to 30 weeks after treatment start for cohort A and 25 to 28 weeks after treatment start for cohort B.)
- Rate of breast conserving surgery (BCS) at the time of definitive surgery(At the date of surgery, estimated at 29 to 32 weeks after treatment start for cohort A and at 27 to 30 weeks after treatment start for cohort B.)
- Conversion of intention for mastectomy to BSC and axillary lymph node dissection (ALND) to sentinel lymph node dissection (SLND) or tailored axillary surgery (TAS) after treatment(At the date of pre-operative interdisciplinary tumor board assessment, estimated at 26 to 32 weeks after treatment start for cohort A and at 24 to 30 weeks after treatment start for cohort B)