Tailored Neoadjuvant Chemoimmunotherapy for Stage I TNBC

A Phase 2 Randomized Pilot Study to Develop Tailored Neoadjuvant Chemoimmunotherapy Strategies in Stage I Triple-negative Breast Cancer (DETENTE-1)

The goal of this clinical trial is to compare the effectiveness of several treatment regimens for stage I triple negative breast cancer before surgery. The main question it aims to answer is if these regimens will reduce or completely remove all cancer cells before surgery.

Inclusion Criteria:

• Must have histologically confirmed invasive triple negative breast cancer as defined by ER/PR <10% and HER2 negative by ASCO/CAP criteria or disease consistent with TNBC by physician assessment, with confirmation by study PI.

• Must have untreated, non-metastatic (M0), cT1 (T1a-T1c) N0 disease. Biopsies of suspicious lymph nodes to confirm nodal status are required.

• Bilateral or multifocal disease can be included as long as all areas have been biopsied and are consistent with invasive triple negative breast cancer. In the case of bilateral or multifocal disease, the tumor with the most advanced T stage should be used to assess eligibility.

• The patient must be ≥ 18 years of age on day of signing informed consent.

• Male participants must agree to use a contraception as detailed in Appendix A of this protocol during the treatment period and for at least 6 months after the last dose of study treatment and refrain from donating sperm during this period.

• A female participant is eligible to participate if she is not pregnant (see Appendix A), not breastfeeding, and if at least one of the following conditions apply:

  • Not a WOCBP as defined in Appendix A; -OR-
  • A WOCBP who agrees to follow the contraceptive guidance in Appendix A during the treatment period and for at least 6 months after the last dose of study treatment.

• The participant (or legally acceptable representative if applicable) provides written informed consent for the trial.

• Provides adequate archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue. Note: If submitting unstained cut slides, newly cut slides should be submitted to the testing laboratory within 14 days from the date slides are cut (see Section 9.3).

• Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

• Patients living with HIV must have well-controlled HIV on ART, defined as:

  • CD4 count ≥350 cells/mm3 at time of screening
  • Must have achieved and maintained virologic suppression. This is defined as an HIV RNA level below 50 or the lower limit of detection using the locally available assay at the time of screening and for at least 12 weeks before screening.
  • It is advised that participants must not have had any AIDS-defining opportunistic infections within the past 12 months
  • Participants on ART must have been on a stable regimen, without changes in drugs or dose modifications, for at least 4 weeks before study entry (Day 1) and agree to continue ART throughout the study
  • The combination ART regimen must not contain any anti-retroviral medications that interact with CYP3A4 inhibitors/inducers/substrates (https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and- drug-interactions-table-substrates-inhibitors-and-inducers)

• Participants who have a history of hepatitis B surface antigen positive are eligible if they have received HBV antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to randomization. Patients should remain on antiviral therapy throughout study interventions and follow local guidelines for HBV antiviral therapy post completion of study intervention.

• Participants with history of hepatitis C virus infection are eligible if HCV viral load is undetectable at screening. Participants must have completed curative antiviral therapy at least 4 weeks prior to randomization.

• Have adequate organ function

Exclusion Criteria:

• A WOCBP who has a positive urine pregnancy test within 72 hours prior to randomization (see Appendix A). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. If 72 hours have elapsed between the screening pregnancy test and the first dose of study treatment, another pregnancy test (urine or serum) must be performed and must be negative for subject to start receiving study medication.

• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137).

• Has received systemic anti-cancer therapy, including investigational agents, prior to randomization.

• If the participant has received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment.

• Has received radiotherapy within 2 weeks of start of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis.

• Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of study drug. Administration of killed vaccines is allowed.

• Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment.

  o Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.

• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.

• Has a known additional malignancy (other than their current breast cancer diagnosis) that is progressing or has required active systemic treatment within the past 3 years.

  o Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.

• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.

• Has a history of non-infectious pneumonitis/interstitial lung disease that required steroids within the previous 5 years or has current pneumonitis/interstitial lung disease.

• Has an active infection requiring systemic therapy.

• Has a known history of active mycobacterium tuberculosis.

• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.

• Has known psychiatric or substance use disorders that would interfere with cooperation with the requirements of the trial.

• Is pregnant, breastfeeding, or is expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment.

• Has significant cardiovascular disease, such as:

  • History of myocardial infarction, acute coronary syndrome or coronary angioplasty/stenting/bypass grafting within the last 6 months
  • Congestive heart failure (CHF) New York Heart Association (NYHA) Class II-IV or history of CHF NYHA class III or IV
  • Angina pectoris requiring anti-anginal medication, uncontrolled arrhythmias, or uncontrolled hypertension (systolic blood pressure ≥ 180mmHg and/or diastolic blood pressure ≥ 100mmHg).