Sacituzumab Govitecan +/- Pembrolizumab In HR+ / HER2 - MBC

Study Overview
=================
Brief Summary
-----------------
This research study is evaluating the safety and effectiveness of Sacituzumab Govitecan with or without Pembrolizumab in metastatic HR+/HER2- breast cancer. The names of the study interventions involved in this study are: Sacituzumab govitecan (IMMU-132) Pembrolizumab (Keytruda®; MK-3475)

Detailed Description
-----------------
The research study procedures include: screening for eligibility, research blood collections, at least two research biopsies, paired research stool collections, and study treatment including evaluations and follow up visits. The names of the study interventions involved in this study are: Sacituzumab govitecan (IMMU-132) Pembrolizumab (Keytruda®; MK-3475) Questionnaires/Data Collection/Sample Collection Participants will be randomized into one of two groups. Group A: Sacituzumab govitecan (IMMU-132) and Pembrolizumab Group B: Sacituzumab govitecan (IMMU-132) Participants will receive study treatment for as long they are benefiting from the therapy. Participants will be followed for the rest of their lives. It is expected that about 110 people will take part in this research study This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational drug or a combination of investigational drugs to learn whether the drug or drug combination works in treating a specific disease. Investigational means that the drug or drug combination is being studied. The U.S. Food and Drug Administration (FDA) has not approved Sacituzumab Govitecan for your specific disease, but it has been approved for other uses. The U.S. Food and Drug Administration (FDA) has not approved Pembrolizumab for your specific disease but it has been approved for other uses.

Official Title
-----------------
Saci-IO HR+: Randomized Phase II Study of Sacituzumab Govitecan With or Without Pembrolizumab in Hormone Receptor-positive (HR+) / HER2- Metastatic Breast Cancer (MBC)

Conditions
-----------------
Invasive Breast Cancer, Metastatic Breast Cancer, HR-Positive Breast Cancer, HER2-negative Breast Cancer

Intervention / Treatment
-----------------
* Drug: Pembrolizumab
* Drug: Sacituzumab Govitecan


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Participants must have histologically or cytologically confirmed invasive breast cancer with unresectable locally advanced or metastatic disease. Participants without pathologic or cytologic confirmation of metastatic disease should have unequivocal evidence of metastasis from physical examination or radiologic evaluation, i.e. visible chest wall disease or metastases on imaging meeting standard radiology criteria (i.e. lymph nodes larger than 1 cm in the short axis diameter). Participants must have HR-positive, HER2-negative breast cancer (ER>1% and/or, PR>1%, HER2-negative per ASCO CAP guidelines) on local pathology review. If a patient has more than one histological result, the most recent sample will be considered for inclusion. Participants must have either progressed on or within 12 months of adjuvant endocrine therapy or have progressed on at least one line of endocrine therapy for metastatic disease, and be considered appropriate candidates for chemotherapy. Participants must have evaluable or measurable disease per RECIST 1.1. For instance, patients with bone only disease will be allowed to participate. Participants must agree to undergo a research biopsy, if tumor is safely accessible, at baseline. Previously collected archival tissue will also be obtained on all participants. Tissue needs to be located and availability confirmed at time of registration. Participants must agree to a mandatory repeat biopsy 3-6 weeks after starting treatment, if tumor is safely accessible. Prior chemotherapy: Participants may have received 0-1 prior chemotherapeutic regimens for metastatic breast cancer and must have been off treatment with chemotherapy for at least 14 days prior to study treatment initiation. If a prior chemotherapy was given for less than 1 cycle, it will not be counted as a prior line. No prior irinotecan or topoisomerase I-containing antibody drug conjugates in the metastatic or neo/adjuvant setting are allowed. All toxicities related to prior chemotherapy must have resolved to CTCAE v5.0 grade 1 or lower, except alopecia can be any grade and neuropathy can be grade 2 or lower. Prior biologic therapy: Patients must have discontinued all biologic therapy at least 14 days prior to study treatment initiation. All toxicities related to prior biologic therapy must have resolved to CTCAE v5.0 grade 1 or lower. Prior targeted therapy: Targeted therapy must have been discontinued ≥ 14 days prior to initiation of study therapy. All toxicities related to prior targeted therapy must have resolved to CTCAE v5.0 grade 1 or lower. Prior radiation therapy: Patients may have received prior radiation therapy. Radiation therapy must be completed at least 7 days prior to the initiation of study treatment (at least 7 days for SRS), and all toxicities related to prior radiation therapy must have resolved to CTCAE v5.0 grade 1 or lower, unless otherwise specified per protocol. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease. Previously treated brain metastases are permitted, with the following provisions: Prior SRS should complete ≥ 7 days before study treatment initiation Prior WBRT should complete ≥ 7 days before study treatment initiation. Any corticosteroid use for brain metastases must have been discontinued for ≥ 7 days prior to study treatment initiation. Participants on bisphosphonates or RANK ligand inhibitors may continue receiving therapy during study treatment and also may initiate therapy with these agents on study if clinically indicated. The subject is ≥ 18 years old. ECOG performance status 0-1 (Karnofsky > 60%). Participants must have normal organ and marrow function as defined below: Absolute neutrophil count ≥1,000/mcL Platelets ≥100,000/mcL Hemoglobin ≥ 9.0 g/dl INR/PT/aPTT ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is in therapeutic range of anticoagulant Total bilirubin ≤1.5 × institutional upper limit of normal (ULN) (or ≤2.0 x ULN in patients with documented Gilbert's Syndrome) AST(SGOT)/ALT(SGPT) ≤2.5 × institutional ULN or ≤5 × institutional ULN for participants with documented liver metastases Serum creatinine ≤1.5 × institutional ULN OR creatinine clearance ≥ 30 mL/min/ 1.73m2 for participants with creatinine levels above institutional ULN. Female subjects of childbearing potential must have a negative serum or urine pregnancy test within 2 weeks prior to study treatment initiation. Childbearing potential is defined as participants who have not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause) and have not undergone surgical sterilization (removal of ovaries and/or uterus). Women of childbearing potential (WOCBP) must agree to use an adequate method of contraception. Contraception is required starting with the first dose of study medication through 180 days (6 months) after the last dose of study medication. Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, and copper intrauterine devices. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception. Hormonal contraceptives are contraindicated for HR+ breast cancer. Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of study treatment with pembrolizumab and 3 months after the last dose of study treatment. The participant must be capable of understanding and complying with the protocol and willing to sign a written informed consent document. Exclusion Criteria: Prior therapy with any anti-PD-1, PD-L1, or PD-L2 agent or sacituzumab govitecan. Prior therapy with irinotecan or topoisomerase I-containing antibody drug conjugates at any time for early stage or metastatic disease. Prior hypersensitivity to the excipients of pembrolizumab or sacituzumab govitecan therapy. Known history of UDP-glucuronosyltransferase 1A1 (UGT1A1) *28 allele homozygosity, which is associated with increased risk for neutropenia and diarrhea related to irinotecan. Note: Concurrent administration of strong UGT1A1 inhibitors or inducers is not allowed during the course of the study. Known brain metastases that are untreated, symptomatic, or require therapy to control symptoms. Major surgery within 2 weeks prior to study treatment initiation. Patients must have recovered from any effects of any major surgery. Uncontrolled, significant intercurrent or recent illness including, but not limited to, ongoing or active infection, uncontrolled non-malignant systemic disease, uncontrolled seizures, or psychiatric illness/social situation that would limit compliance with study requirements in the opinion of the treating investigator. Participant has a medical condition that requires chronic systemic steroid therapy (> 10 mg of prednisone daily or equivalent) or any other form of immunosuppressive medication (including disease modifying agents) and has required such therapy in the last 2 years. Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic therapy. Participant has documented history of autoimmune disease or syndrome that currently requires systemic steroids or immunosuppressive agents. History of (non-infectious) pneumonitis/interstitial lung disease that required steroids or current pneumonitis/interstitial lung disease. Individuals with a history of a second malignancy are ineligible except for the following circumstances. Individuals with a history of other malignancies are eligible if they have been disease-free for at least 3 years or are deemed by the investigator to be at low risk for recurrence of that malignancy. Individuals with the following cancers that have been diagnosed and treated within the past 3 years are eligible: cervical/prostate carcinoma in situ, superficial bladder cancer, non-melanoma cancer of the skin. Patients with other cancers diagnosed within the past 3 years and felt to be at low risk of recurrence should be discussed with the study principal investigator to determine eligibility. Participant has a known history of human immunodeficiency virus (HIV), Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as detected HCV RNA [qualitative]) infection. HIV-positive participants are ineligible due to the potential for pharmacokinetic interactions of combination antiretroviral therapy with study drugs and the increased risk of fatal infections. Note: No testing for HIV, Hepatitis B, or Hepatitis C is required unless mandated by local health authority. The participant has received a live vaccine within 28 days prior to study treatment initiation. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine. The use of the inactivated seasonal influenza vaccine is allowed. 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. It is unknown whether pembrolizumab is excreted in human milk. Since many drugs are excreted in human milk, and because of the potential for serious adverse reactions in the nursing infant, participants who are breast-feeding are not eligible for enrollment.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sacituzumab Govitecan + Pembrolizumab<br>The research study procedures include: screening for eligibility, research blood collections, at least two research biopsies, paired research stool collections, and study treatment including evaluations and follow up visits. Each Cycle =21 Days Sacituzumab Govitecan (iv) fixed dose, administered twice per cycle Pembrolizumab (iv) fixed dose administered once per cycle | Drug: Pembrolizumab<br>* (iv) fixed dose, administered once per cycle<br>* Other names: Keytruda;Drug: Sacituzumab Govitecan<br>* (iv) fixed dose, administered twice per cycle<br>* Other names: TRODELVY;|
| Experimental: Sacituzumab Govitecan<br>The research study procedures include: screening for eligibility, research blood collections, at least two research biopsies, paired research stool collections, and study treatment including evaluations and follow up visits. - Sacituzumab Govitecan (iv) fixed dose, administered twice per cycle | Drug: Sacituzumab Govitecan<br>* (iv) fixed dose, administered twice per cycle<br>* Other names: TRODELVY;|
| Experimental: Retreatment<br>Participants who have attained a confirmed complete response (CR) who have been treated for at least 24 weeks on protocol therapy and had at least three cycles (with pembrolizumab and sacituzumab govitecan (Arm A) or sacituzumab govitecan alone (Arm B)) beyond the date when the initial CR was declared may be eligible for additional sacituzumab govitecan and/or pembrolizumab therapy if they progress after stopping study treatment. This retreatment is termed the Second Course Phase of this study and is only available if the study remains open and the subject meets protocol-specified conditions. | Drug: Pembrolizumab<br>* (iv) fixed dose, administered once per cycle<br>* Other names: Keytruda;Drug: Sacituzumab Govitecan<br>* (iv) fixed dose, administered twice per cycle<br>* Other names: TRODELVY;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival | Compare the progression-free survival (PFS) of sacituzumab govitecan with pembrolizumab to that of sacituzumab govitecan alone. PFS is defined as the time from study randomization to disease progression, according to RECIST 1.1 or medical judgment, the latter based on established clinical parameters, such as rising tumor markers and physical exam evidence of progression, i.e. worsening chest wall disease, or death due to any cause, whichever occurred first. Patients alive without disease progression are censored at the date of last disease evaluation. | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate | Compare the efficacy of sacituzumab govitecan with pembrolizumab to that of sacituzumab govitecan alone by assessing Overall Response Rate (ORR) by RECIST 1.1 | 3 years | 
| Overall Survival | Compare the efficacy of sacituzumab govitecan with pembrolizumab to that of sacituzumab govitecan alone by assessing overall survival (OS), defined as the time from randomization (or registration) to death due to any cause with censoring at date last known alive, will be reported with Kaplan Meier estimates | 3 years | 
| Clinical Benefit Rate | Compare the efficacy of sacituzumab govitecan with pembrolizumab to that of sacituzumab govitecan alone by assessing clinical benefit rate (CBR). CBR defined as CR, PR or stable disease for ≥ 24 weeks according to RECIST 1.1 | 3 years | 
| Time to Progression | Compare the efficacy of sacituzumab govitecan with pembrolizumab to that of sacituzumab govitecan alone by assessing time to progression | 3 years | 
| Duration of Response | Compare the efficacy of sacituzumab govitecan with pembrolizumab to that of sacituzumab govitecan alone by assessing the duration of response (the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented or death due to any cause) | 3 years | 
| Number of Participants with Treatment-Related Adverse Events as Assessed by CTCAE v5.0 | Evaluate the safety and tolerability of sacituzumab govitecan and pembrolizumab compared to sacituzumab govitecan alone by monitoring adverse events, including immune-related adverse events. Summarized by maximum grade and by treatment arm. | 3 years | 
| Progression-free survival in PD-L1-positive population | Compare the PFS of sacituzumab govitecan with pembrolizumab to that of sacituzumab govitecan alone in the subgroup of patients with PD-L1-positive HR+ / HER2- MBC. | 3 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Invasive Breast Cancer, Metastatic Breast Cancer, HR-Positive Breast Cancer, HER2-negative Breast Cancer