Clinical Trials /

Pre-operAtive Non-Anthracycline Chemotherapy, Durvalumab +/- RAdiation Therapy in Triple Negative Breast Cancer

NCT03872505

Description:

This phase II randomized trial is for patients with clinical stage II-III, ER and PR <10%, HER2-negative invasive breast carcinoma (triple negative breast cancer) for whom adjuvant RT is planned and pre-operative RT is deemed feasible by the treating radiation oncologist. Subjects will be randomized into arm A or B and treatment will last for 16 weeks. Both groups will receive Durvalumab 750mg IV Q2 weeks x 2 then a biopsy prior to durvalumab 1500mg IV Q4 weeks x 3 with paclitaxel and carboplatin IV weekly x 12. Arm B will receive radiation (24 Gy total) starting with the second durvalumab dose every other day (8Gy per fraction) for one week. Following treatment, subjects will receive SOC breast surgery and continue on to physician's choices SOC treatment during the 3 year follow up period. This study hopes to explore the impact of checkpoint blockade administration with a non- anthracycline chemotherapy regimen plus RT on post-surgery pathologic complete response (pCR) rate in the breast and axilla (ypT0/Tis ypN0) following 12 weeks of treatment and surgery.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pre-operAtive Non-Anthracycline Chemotherapy, Durvalumab +/- RAdiation Therapy in Triple Negative Breast Cancer
  • Official Title: A Randomized Phase II Study Evaluating Pathologic Response Rates Following Pre-operAtive Non-Anthracycline Chemotherapy, Durvalumab (MEDI4736) +/- RAdiation Therapy (RT) in Triple Negative Breast Cancer (TNBC): The PANDoRA Study.

Clinical Trial IDs

  • ORG STUDY ID: IIT2018-17-McArthur-TCDRT
  • NCT ID: NCT03872505

Conditions

  • Breast Cancer
  • Triple Negative Breast Cancer

Interventions

DrugSynonymsArms
DurvalumabImfimziChemotherapy + Durvalumab
CarboplatinChemotherapy + Durvalumab
PaclitaxelChemotherapy + Durvalumab

Purpose

This phase II randomized trial is for patients with clinical stage II-III, ER and PR <10%, HER2-negative invasive breast carcinoma (triple negative breast cancer) for whom adjuvant RT is planned and pre-operative RT is deemed feasible by the treating radiation oncologist. Subjects will be randomized into arm A or B and treatment will last for 16 weeks. Both groups will receive Durvalumab 750mg IV Q2 weeks x 2 then a biopsy prior to durvalumab 1500mg IV Q4 weeks x 3 with paclitaxel and carboplatin IV weekly x 12. Arm B will receive radiation (24 Gy total) starting with the second durvalumab dose every other day (8Gy per fraction) for one week. Following treatment, subjects will receive SOC breast surgery and continue on to physician's choices SOC treatment during the 3 year follow up period. This study hopes to explore the impact of checkpoint blockade administration with a non- anthracycline chemotherapy regimen plus RT on post-surgery pathologic complete response (pCR) rate in the breast and axilla (ypT0/Tis ypN0) following 12 weeks of treatment and surgery.

Trial Arms

NameTypeDescriptionInterventions
Chemotherapy + DurvalumabActive ComparatorArm A: Carboplatin, Paclitaxel and Durvalumab
  • Durvalumab
  • Carboplatin
  • Paclitaxel
Chemo + Durvalumab + Radiation TherapyExperimentalArm B: Carboplatin, Paclitaxel and Durvalumab + Radiation Therapy
  • Durvalumab
  • Carboplatin
  • Paclitaxel

Eligibility Criteria

        Inclusion Criteria:

          1. Male/female patients with histologically confirmed invasive breast cancer, ER <10%, PR
             <10% and HER2-negative for whom adjuvant RT is planned and in whom pre-operative RT is
             feasible.

          2. Clinical stage II-III by the AJCC 8th definition, any nodal status (cT2-4N0 or
             cT1-4N1-3), biopsies of clinically suspicious lymph nodes to confirm nodal status is
             encouraged.

          3. Capable of giving signed informed consent which includes compliance with the
             requirements and restrictions listed in the informed consent form and in this
             protocol. Written informed consent and any locally required authorization obtained
             from the patient/legal representative prior to performing any protocol-related
             procedures, including screening evaluations.

          4. At least 18 years of age on the day of signing informed consent.

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

          6. Body weight >30kg.

          7. Have provided 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.

          8. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.

          9. Have adequate organ function as defined in the following table (Table 1). Specimens
             must be collected within 10 days prior to the start of study treatment.

         10. Patient is willing and able to comply with the protocol for the duration of the study
             including undergoing treatment and scheduled visits and examinations including follow
             up.

         11. Patients with multifocal, multicentric or bilateral breast cancer are permitted if all
             suspicious foci have been biopsied and deemed "triple negative" per criterion 1.

             Male participants:

         12. A male participant must agree to use a contraception as detailed in Appendix C 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.

             Female participants:

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

               1. Not a woman of childbearing potential (WOCBP) as defined in Appendix C OR

               2. A WOCBP who agrees to follow the contraceptive guidance in Appendix C during the
                  treatment period and for at least 6 months after the last dose of study
                  treatment.

        Exclusion Criteria:

          1. A WOCBP who has a positive urine pregnancy test within 72 hours prior to randomization
             (see Appendix C). If the urine test is positive or cannot be confirmed as negative, a
             serum pregnancy test will be required.

          2. 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).

          3. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment.
             Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone
             replacement therapy) is acceptable.

          4. Major surgical procedure within 28 days prior to the first dose of study drug.

          5. History of allogenic organ transplantation.

          6. Has received a live vaccine within 30 days prior to the first dose of study drug.
             Examples of live vaccines include, but are not limited to, the following: measles,
             mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus
             Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection
             are generally killed virus vaccines and are allowed; however, intranasal influenza
             vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed. Note:
             Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to
             30 days after the last dose of IP.

          7. Participation in another clinical study with an investigational product during the
             last 4 weeks, unless it is an observational (non-interventional) clinical study or
             during the follow-up period of an interventional study.

          8. Current or prior use of immunosuppressive medication within 14 days before the first
             dose of durvalumab. The following are exceptions to this criterion:

               1. Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra
                  articular injection)

               2. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
                  prednisone or its equivalent

               3. Steroids as premedication for hypersensitivity reactions (e.g., CT scan
                  premedication)

          9. History of another primary malignancy except for:

               1. Malignancy treated with curative intent and with no known active disease ≥5 years
                  before the first dose of IP and of low potential risk for recurrence

               2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
                  of disease

               3. Adequately treated carcinoma in situ without evidence of disease

         10. Known allergy or hypersensitivity to any of the study drugs or any of the study drug
             excipients.

         11. Active or prior documented autoimmune or inflammatory disorders (including
             inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with
             the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome,
             or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid
             arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this
             criterion:

               1. Patients with vitiligo or alopecia

               2. Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on
                  hormone replacement

               3. Any chronic skin condition that does not require systemic therapy

               4. Patients without active disease in the last 5 years may be included but only
                  after consultation with the study physician

               5. Patients with celiac disease controlled by diet alone

         12. Has a history of (non-infectious) pneumonitis that required steroids or has current
             pneumonitis.

         13. Has an active infection requiring systemic therapy.

         14. History of active primary immunodeficiency.

         15. Known active infection including tuberculosis (clinical evaluation that includes
             clinical history, physical examination and radiographic findings, and TB testing in
             line with local practice), hepatitis B, hepatitis C, or human immunodeficiency virus .
             Patients with a past or resolved HBV infection are eligible. Patients positive for
             hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative
             for HCV RNA.

         16. Uncontrolled intercurrent illness, including but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
             angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic
             gastrointestinal conditions associated with diarrhoea, or psychiatric illness/social
             situations that would limit compliance with study requirement, substantially increase
             risk of incurring AEs or compromise the ability of the patient to give written
             informed consent.

         17. Female patients who are pregnant or breastfeeding or male or female patients of
             reproductive potential who are not willing to employ effective birth control from
             screening to 90 days after the last dose of durvalumab monotherapy.

         18. Prior randomization or treatment in a previous durvalumab clinical study regardless of
             treatment arm assignment.

         19. Stage IV (metastatic) breast cancer

         20. Inflammatory breast cancer
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Pathological complete response rate in the breast and axilla
Time Frame:20 weeks from randomization
Safety Issue:
Description:Proportion of subjects without residual invasive cancer in the breast and axilla from randomization to definitive surgery. Measured as the lack of residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy at the time of definitive surgery.

Secondary Outcome Measures

Measure:Pathological complete invasive and in situ response rate (breast and axilla)
Time Frame:20 weeks from randomization
Safety Issue:
Description:Proportion of subjects without residual invasive and in situ cancer in the breast and axilla disease from randomization to definitive surgery. - Residual invasive cancer and in situ disease defined based on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy by pathological assessment.
Measure:Proportion of subjects with pathological invasive complete response in the breast only
Time Frame:20 weeks from randomization
Safety Issue:
Description:Proportion of subjects without residual invasive cancer in the breast from randomization to definitive surgery. - Residual invasive breast cancer defined based on hematoxylin and eosin evaluation of the complete resected breast specimen following completion of neoadjuvant systemic therapy by pathological assessment.
Measure:Residual Cancer Burden (RCB)
Time Frame:20 weeks from randomization
Safety Issue:
Description:Proportion of subjects with RCB 0-I, II or III from randomization to definitive surgery. -Residual Cancer Burden defined based on the RCB index, a component of four pathological parameters: bi-dimensional diameter of primary tumor bed, percent of cellularity in the tumor bed, number of involved lymph nodes and size of the largest nodal metastasis. The RCB possible scores are: RCB 0 (pCR), RCB I, RCB II, RCB III.
Measure:Event Free Survival
Time Frame:36 months from randomization
Safety Issue:
Description:Mean difference in time (in months) from randomization to any of the following events progression of disease that precludes surgery, local or distant recurrence, or death due to any cause.
Measure:Invasive disease-free survival (IDFS)
Time Frame:33 months from surgery
Safety Issue:
Description:Mean difference in time (in months) from date of surgery (date of no disease) to the first documentation of invasive progressive disease or death.
Measure:Overall survival
Time Frame:36 months from randomization
Safety Issue:
Description:Mean difference in time (in months) from randomization to death.
Measure:Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time Frame:24 weeks from treatment initiation
Safety Issue:
Description:Incidence and severity of adverse events (AE) and serious adverse events (SAE) from cycle 1 day 1 until 30 days post-surgery. -AEs and SAEs based on CTCAE 5.0
Measure:Frequency of adjuvant treatment after surgery
Time Frame:36 months from randomization
Safety Issue:
Description:Average number of subjects receiving adjuvant treatment after surgery.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Cedars-Sinai Medical Center

Trial Keywords

  • breast cancer
  • durvalumab
  • immunotherapy
  • triple negative
  • HER2 negative
  • ER/PR negative
  • carboplatin
  • radiation therapy
  • paclitaxel
  • neoadjuvant
  • stage II breast cancer
  • stage III breast cancer

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