Intratumoral INT230-6 Followed by Neoadjuvant Immuno-chemotherapy in Patients With Early TNBC. INVINCIBLE-4-SAKK

Triple-negative Breast Cancer Clinical Trial

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06358573
• Other study ID #: SAKK 66/22
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: June 30, 2024
• Est. completion date: December 2029

Study information

• Verified date: April 2024
• Source: Swiss Group for Clinical Cancer Research
• Contact: Katrin Eckardt, PhD
• Phone: +41 31 389 91 91
• Email: trials[@]sakk.ch
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 54
• Est. completion date: December 2029
• Est. primary completion date: March 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• 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: cT2-4c N0-3 M0.

• Multifocal and multicentric primary tumors are allowed and the tumor with the most advanced T stage should be used to assess the 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 =2cm 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 or serum creatinine = 1.5x ULN.

• Adequate cardiac function: Left ventricular Ejection Fraction (LVEF) = 50% as determined by echocardiography (ECHO)

• Adequate coagulation function:

• INR = 1.5 x ULN unless patient is receiving anticoagulant therapy

• aPTT = 1.5 x ULN unless patient is receiving anticoagulant therapy

• If 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 6 months after the last dose of INT230-6 or 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 during trial treatment and until 6 months after the last dose of INT230-6 or standard of care treatment (www.swissmedicinfo.ch).

Exclusion Criteria:

• Inflammatory Breast Cancer cT4d

• 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 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 INT230-6. 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.

• 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.

Related Conditions & MeSH terms

• Breast Neoplasms
• TNBC - Triple-Negative Breast Cancer
• Triple Negative Breast Neoplasms
• Triple-negative Breast Cancer

Intervention

Drug:
• INT230-6
INT230-6 is a formulation consisting of an proprietary amphiphilic cell penetration enhancer molecule, 8-((2-hydroxybenzoyl)amino)octanoate, also referred to as SHAO, combined with cisplatin and vinblastine sulfate. The IMP is without marketing authorization in Switzerland and anywhere in the world.

Other:
• neoadjuvant immuno-chemotherapy
Standard of care

Locations

Country	Name	City	State
Switzerland	Tumor Zentrum Aarau	Aarau
Switzerland	St. Claraspital	Basel
Switzerland	Istituto Oncologico della Svizzera Italiana (IOSI)	Bellinzona
Switzerland	Kantonsspital Graubünden	Chur
Switzerland	Kantonsspital Baselland	Liestal
Switzerland	Kantonsspital St. Gallen	St. Gallen
Switzerland	TBZO - Tumor- & Brustzentrum Ostschweiz	St. Gallen
Switzerland	Kantonsspital Winterthur	Winterthur
Switzerland	Universitätsspital Zürich - Klinik für Gynäkologie	Zürich

Sponsors (1)

Lead Sponsor	Collaborator
Swiss Group for Clinical Cancer Research

Country where clinical trial is conducted

Switzerland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Pathological complete response (pCR) in the primary tumor (ypT0/Tis) and affected lymph nodes (ypN0).	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.	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.
Secondary	pCR (invasive and in-situ, only invasive, respectively) in the breast	No invasive and no in situ breast cancer in primary tumor ypT0 No invasive breast cancer in affected lymph nodes ypN0 The endpoint will be analyzed based on the resected patients set. The endpoint is evaluated according to the assessment of the local pathologist.	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.
Secondary	pCR in lymph nodes	No invasive and no in situ breast cancer in primary tumor ypT0 No invasive breast cancer in affected lymph nodes ypN0 The endpoint will be analyzed based on the resected patients set. The endpoint is evaluated according to the assessment of the local pathologist.	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.
Secondary	Pattern of non pCR	Pattern in the remaining tumor is for example visible circle or tumor border, moon shaped residual tumor, islands of tumor in sea of necrosis, tumor streaks radiating from the main tumor into the surrounding tissue, single tumor cells (e.g. in lobulary tumor).; This endpoint will be analyzed based on the subset of patients in the resected patients set who did not achieve pCR in the primary tumor (any invasive cancer in primary tumor).	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.
Secondary	Overall response according to RECIST v1.1	Overall response (OR) is defined as complete response (CR) or partial response (PR) in the last pre-surgery tumor assessment compared with baseline MRI evaluated according to RECIST v1.1. In the subset of patients in cohort A additionally the change from baseline to the MRI between the 2nd injection and start of immunochemotherapy will be evaluated.; The Criteria for RECIST v1.1. will be used with one modification: the injected lesion will still be measured/evaluated for this endpoint. Rationale: For a large proportion of the patients the injected lesion will be the only tumor lesion (cT2-4, cN0) or it will contain the majority of the tumor burden (in cN1 cases). Therefore, not evaluating this lesion would result in to many patients lost for this endpoint.; This endpoint will be analyzed based on the FAS (Full Analysis Set).	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.
Secondary	Radiological tumor response using two perpendicular diameters	Bidimensional assessment is only done for the largest (injected) primary tumor in the breast (not of satellite lesions and not of lymph nodes): we use the largest diameter measured in MRI and its perpendicular second diameter in the same MRI image. The two diameters are multiplied. Radiological tumor response in the last pre-surgery MRI is defined as follows: CR: disappearance of the whole lesion; PR: > 50% decrease from baseline; PD: > 25% increase from baseline or appearance of new lesions in the breast This endpoint will be analyzed based on the FAS (Full Analysis Set).	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.
Secondary	Event free survival (EFS)	EFS is defined as the time from randomization to any of the following events, whichever comes first: Progression of disease that precludes surgery; Local or distant recurrence; Second primary malignancy (breast or other cancers). The following events are excluded: basal or squamous cell carcinoma of the skin, carcinoma in situ of the cervix lobular carcinoma in situ of the breast (LCIS), ductal carcinoma in situ of the breast (DCIS) and myeloplastic syndrome; Death due to any cause Patients not experiencing an event will be censored at the date of the last available assessment before initiation of a subsequent treatment, if any.; This endpoint will be analyzed based on the FAS.	): From the date of randomization until the date of the event of interest up to 3 years after surgery.
Secondary	Rate of breast conserving surgery (BCS) at the time of definitive surgery	Proportion of patients with BCS at the time of definitive surgery. This endpoint will be analyzed based on the resected patients set.	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.
Secondary	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	This endpoint is defined as the change from intended mastectomy at baseline to BCS at time point of definitive surgery or from ALND to SLND or TAS.; It will be analyzed based on the subgroup of the patients in the resected patients set for which mastectomy or ALND was foreseen at registration.	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