Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Breast Neoplasms

Triple Negative Breast Neoplasms

Breast Diseases

Skin Diseases

Antineoplastic Agents

All Drugs and Chemicals

Pembrolizumab

Immunomodulating Agents

Ruth Sacks, MD

Ashley Trumbull

This research study is a prospective, single arm, pilot study, designed to evaluate the correlation between the immune and clinical responses of subjects with untreated Stage II-III triple negative breast cancer (TNBC) undergoing standard of care neoadjuvant chemo- immunotherapy.

Primary Objective:

I. To determine whether standard of care neoadjuvant chemo-immunotherapy leads to the induction of a pro-inflammatory cytokine milieu (characterized by high IFN- γ, IFN-α, IL-6 and low TGF-β) in the blood which is induced within 24 hours of treatment initiation, persists through the course of the therapy and is associated with pathologic complete response in the tissue.

Secondary Objectives:

I. To determine whether the spatially resolved tissue TGF-β induced transcriptomic signatures or lack of innate interferon inducible genes/effector CD8 modules are abundant in tumors from TNBC patients that do not show pathologic complete response in the tissue at the end of standard of care neoadjuvant chemo- immunotherapy.

Evaluating and Monitoring Immune and Clinical Responses in Early-Stage Triple Negative Breast Cancer Undergoing Neoadjuvant Chemo-immunotherapy With Pembrolizumab

The change in the cytokine milieu specifically IFN-γ, IFN-α, IL-6 and TGF-β in the blood during standard of care neoadjuvant chemo-immunotherapy and its association with pathologic complete response in the tissue

The transcriptomic signatures of TGF-β induced genes and innate interferon inducible genes/effector CD8 in the tissue specimens collected at baseline (archival tissue obtained prior to standard of care neoadjuvant chemo- immunotherapy) and after completion of treatment at the time of surgery.

National Cancer Institute (NCI)

Emory University

Principal Investigator

Temozolomide

Olaparib

Antineoplastic Agents, Alkylating

Alkylating Agents

Poly(ADP-ribose) Polymerase Inhibitors

Enzyme Inhibitors

Temozolomide: 50 mg/m2 daily in cycles of 21 days

Temozolomide 75 mg/m2 day 1 to day 7 with Olaparib 200 mg BID, oral, day 1 to day 7 in cycles of 21 days

Temozolomidewill be administered orally for 7 days (D) every 21 days until progression of the disease in both arms.

Olaparib will be administered orally twice daily in treatment arm 2.

Amy Abel

Don Morris, MD

Michelle Kan

Don Morris, MD, PhD

This is a randomized phase II study to evaluate the disease control rate (DCR) of patients with metastatic or locally advanced METHYLATED 06-methylguanine-DNA methyltransferase (MGMT) with triple-negative breast cancer (TNBC) treated with Temozolomide ± Olaparib. Patients will be randomized 1:1 to Treatment Arm 1 (temozolomide treatment) or Arm 2 (temozolomide plus olaparib treatment).

Background and Rationale:

Breast cancer (BC) is the second leading cause of cancer deaths among Canadian women. Treatment of BC is based on the expression of estrogen receptor (ER), progesterone receptor (PgR), and amplification of human epidermal growth factor receptor 2 (HER2), in conjunction with traditional clinical-pathological features such as tumor grade, size, and lymph node status. Patients whose tumours lack ER, PgR and show no overexpression of HER2, collectively termed triple negative breast cancer (TNBC), account for 15-20% of all BC diagnoses. These tumours do not respond to hormone therapy or HER2 targeted agents and are treated instead with traditional chemotherapeutic agents, which are non-specific and are associated with potentially significant toxicity.

The alkylating agent Temozolomide (TMZ) is an oral chemotherapy drug that damages DNA by adding methyl groups to the O6- and N7- positions of guanine (O6-meG and N7-meG, respectively) and the N3- position of adenine (N3-meA). 06-methylguanine-DNA methyltransferase (MGMT) repairs O6- adducts caused by TMZ during DNA replication, resulting in cell survival. MGMT expression is commonly decreased in cancer due to promoter methylation (mMGMT), leading to enhanced TMZ-induced cell death. MGMT promoter methylation has been noted in many human tumours, including BC. Intriguingly, prevalence of mMGMT has been shown to be higher in TNBC relative to hormone receptor positive BCs. TMZ has been explored as a potential treatment option for BC patients.

In normal cells, the protein poly (ADP-ribose) polymerase (PARP) is involved in repairing the N7-meG DNA lesions caused by TMZ to ensure cell survival. Although TMZ toxicity is predominantly manifested by non-repair of the O6-meG adducts due to low/deficiency of MGMT, inhibition of PARP using a PARPi, such as Olaparib, has been shown to enhance TMZ's cytotoxicity. When PARP is unable to repair DNA damage, significant replication stress ensues that ultimately causes formation of double-strand breaks (DSBs), which can be repaired by homologous recombination (HR) to promote cell survival. Critical to the HR repair process, and cell survival in the absence of PARP, is a functional BRCA1 and BRCA2. In the absence of these proteins, the DSBs caused by replication stress cannot be repaired, resulting in cell death. Thus, individuals with germline mutations in BRCA1/2 genes (BRCA-positive) are extremely sensitive to PARPi. Approximately 10% of TNBC patients carry a germline BRCA mutation and therefore may be eligible for a PARP inhibitor such as olaparib.

Recently, early phase trials (clinicaltrials.gov: NCT01009788, NCT01618136, NCT01506609) have aimed to evaluate TMZ in combination with a PARPi in BC. The early trials showed promising results with Veliparib (PARPi) in combination with Temozolomide, with a 25% objective response rate (ORR), with a 50% clinical benefit rate (CBR) seen in BRCA-positive patients; however, recent results from the BROCADE study (NCT01506609) found that Veliparib plus TMZ was inferior to the other treatment arms evaluated but still showed a CBR of 73%, with 1 complete and 19 partial responses noted (22% of patients) in BRCA-positive. Importantly, this trial did not evaluate mMGMT status in participants' tumour samples. Although not in BC, the recent findings that Veliparib in combination to TMZ in glioblastomas found that Veliparib significantly enhances the efficacy of TMZ in mMGMT tumours in patient-derived xenograft in vivo models, have been incorporated into an ongoing phase II/III clinical trial (NCT02152982), with the results still not being reported. Overall, the preclinical research findings strongly suggest that TMZ and PARPi combination may benefit BC patients with mMGMT tumours. Currently, there are no known clinical trials evaluating TMZ with the only clinically approved PARPi's, Olaparib and Talazoparib, in BC.

Study Design and Duration:

This is a randomized phase II study to evaluate DCR of patients with metastatic or locally advanced mMGMT TNBC treated with TMZ ± Olaparib. Patients will be randomized 1:1 to Treatment Arm 1 or 2.

Arm 1: Temozolomide (Day 1- 21 of 21-day cycles) Arm 2: Temozolomide (Day 1-7 of 21-day cycles) plus olaparib (Day 1-7 of 21 day cycles) Duration of treatment: Until disease progression, unacceptable toxicity, withdrawal of consent by patient.

Duration of study: 5 years; the study will end when either all patients die, or 3 years have passed since the last patient started study treatment, whichever comes first.

Temozolomide Monotherapy or in Combination With Olaparib in Patients With Triple Negative Breast Cancer (TNBC)

A Randomized Phase II Study of Temozolomide Monotherapy or in Combination With Olaparib in Patients With METHYLATED 06-Methylguanine-DNA Methyltransferase (MGMT) Pre-Treated Triple Negative Breast Cancer (TNBC)

Evaluation of promoter methylation and immunohistochemistry (IHC) targets relevant to MGMT and PARP repair pathways to identify patients most likely to derive benefit from temozolomide ± Olaparib.

To determine whether tumor BRCAness phenotype is associated with disease control rate in patients with mMGMT TNBC treated with temozolomide ± olaparib.

To determine whether tumor BRCAness phenotype is associated with progression-free survival in patients with mMGMT TNBC treated with temozolomide ± olaparib.

To investigate whether tumour BRCAness phenotype is associated with overall survival in patients with mMGMT TNBC treated with temozolomide ± olaparib.

To determine the time duration between the radiographic documentation of complete response or partial response or stable disease (whichever is recorded first) until the first date that the progressive disease is documented or death in patients with BRCAness phenotype.

To determine DCR by assessing complete/partial response or stable disease, as per RECIST 1.1 in patients with mMGMT TNBC treated with Temozolomide ± Olaparib.

To determine progression-free survival (PFS) of patients with mMGMT TNBC treated with Temozolomide ± Olaparib.

To determine OS by measuring the time interval from the date of the first dose of the study treatment until death due to any cause. Subjects who are still alive will be censored on the date of last contact.

To determine the number of adverse events related to Temozolomide ± Olaparib treatment according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0, effective November 27, 2017 \[Common Terminology Criteria for Adverse Events (CTCAE).

To determine the time duration between the radiographic documentation of complete response or partial response or stable disease (whichever is recorded first) until the first date that the progressive disease is documented or death.

AHS Cancer Control Alberta

Infections

Respiratory Tract (Lung and Bronchial) Diseases

Influenza, Human

Vaccines

Successive cohorts of participants (3 participants per tumor type per cohort) will each be started on a fixed dose of the influenza vaccine. For the first cohort, patients will receive Fluzone Quadrivalent - (Sanofi Pasteur) - 60mcg/0.5mL (standard dose IT flu shot, or dose level 0) intratumorally on day -6 +/- 1 day and day 0 or 1. For the second cohort, patients will receive Fluzone High-Dose Quadrivalent - (Sanofi Pasteur) - 240mcg/0.7mL (high dose IT flu shot, or dose level 1) intratumorally on day -6 +/- 1 day and day 0 or 1. has context menu

Fluzone Quadrivalent

Angela Limburg, RN, BSN

Angela Limburg

Ruta Rao, MD

This Phase 1 study will assess the safety and efficacy (usefulness) of administering 2 doses of seasonal flu vaccine directly into breast cancer tissue (primary tumor), and will study the tumor and whole body response to the vaccine. If the tumor is palpable (able to fee by touch), the vaccine will be administered by a Surgeon/oncologist in the outpatient floor - both experienced and trained. If not palpable, the procedure will be done via guided Ultrasound by our Breast Radiologist -- both experienced and trained. Women with triple-negative (TNBC) and HER2+ types of breast cancer will be eligible for enrollment. Up to 18 subjects may be enrolled at Rush. Successive groups of 3 subjects per breast cancer type will be given increasing doses of vaccine. There are 3 potential dosing groups (half-dose, full dose, and high dose). Blood, stool (optional), and tumor tissue samples will be collected and tested. The active participation period is from one week prior to starting chemotherapy through three months post surgery.

A Study to Evaluate the Intratumoral Influenza Vaccine Administration in Patients With Breast Cancer

A Phase I Study to Evaluate the Intratumoral Influenza Vaccine Administration in Patients With Breast Cancer

The primary objective of this trial is to assess the safety of intratumoral (IT) influenza vaccine administration in patients with breast cancer receiving neoadjuvant chemotherapy, by evaluating the percentage of patients experiencing dose- limiting toxicity (DLT).

Rush University Medical Center

Study Principal Investigator

Symptoms and General Pathology

Pathologic Complete Response

Antirheumatic Agents

Paclitaxel

Cyclophosphamide

Doxorubicin

Liposomal doxorubicin

Hormones

Albumin-Bound Paclitaxel

Goserelin

Prolactin Release-Inhibiting Factors

Antineoplastic Agents, Hormonal

Goserelin 3.6 mg depot injection will be administered subcutaneously every month along with standard chemotherapy regimen: AC-P: Doxorubicin 60 mg/m2 IV plus cyclophosphamide 600 mg/m2 every 3 weeks for four cycles, followed by paclitaxel 80 mg/m2 by 1 hour infusion every week for 12 weeks. Each cycle is 21 days.

Standard chemotherapy regimen: AC-P: Doxorubicin 60 mg/m2 IV plus cyclophosphamide 600 mg/m2 every 3 weeks for four cycles, followed by paclitaxel 80 mg/m2 by 1 hour infusion every week for 12 weeks. Each cycle is 21 days.

Goserelin is Luteinizing hormone releasing hormone (LHRH) analogue.

Kyrillus S Shohdy, MD

Loay Kassem, MD

This is a phase II randomized trial that will evaluate the effect of adding LHRH analogue, goserelin, to the standard neoadjuvant chemotherapy to patients with triple negative breast cancer. Targeting LHRH might decrease resistance to chemotherapeutic agents in the neoadjuvant setting and increases clinical and pathological response rates. Additionally, exploring potential surrogate markers (as AR and LHRH receptors) for molecular distinct subtypes of TNBC.

Neoadjuvant chemotherapy (NACT) is the mainstay of treatment of locally advanced TNBC and some selected early cases followed by surgery with or without adjuvant radiotherapy. NACT is aimed to induce pathologic complete response (pCR) in tumor and lymph nodes, pCR is proofed to be a surrogate and reliable predictive factor of survival rates in TNBC. This study will evaluate the effect of adding LHRH analogue, goserelin, to the standard neoadjuvant chemotherapy. Following completion of neoadjuvant therapy, patients will undergo breast conservative surgery or mastectomy. Post-neoadjuvant chemotherapy axillary staging will be required, but the choice of the procedure will be at the physician's discretion. Postoperative radiation therapy will be given at the physician's discretion. The use of partial breast irradiation techniques will not be allowed. The primary endpoint will be the rate of pathologic complete response. The secondary endpoints will be 3-year-disease free survival, clinical response and toxicity. Exploratory endpoints will be correlation of the LHRH receptor expression level with the pCR. The sample size for the trial will be 180 patients accrued over a period of 2 years. Definitive analysis of the primary endpoints is expected at year 3.

Neoadjuvant Goserelin for Triple Negative Breast Cancer

Prospective Phase II Randomized Trial of Evaluating the Effect of Adding LHRH Analogue to the Neoadjuvant Chemotherapy Treatment of Triple Negative Breast Cancer on Pathologic Complete Response (pCR) Rates

The primary endpoint will be the pathologic complete response rate (pCR), defined as no residual invasive tumor in both the breast and axilla (and including in situ residual; ypT0/is, ypN0).

Incidence of LHRH-positive and/or AR-positive cases among TNBC

Estimated 3 years RFS rates in the 2 arms (RFS events will include locoregional recurrence, distant recurrence, contralateral breast cancer and death from any cause).

All grade and high grade adverse events rate in both arms

Ovarian failure rates at 2 years in both groups (defined as the absence of menses in the preceding 6 months and levels of follicle-stimulating hormone (FSH) in the postmenopausal range).

Kasr El Aini Hospital

Micronutrients

Hematinics

Vitamins

Folic Acid

Mirvetuximab soravtansine

Vitamin B Complex

Maytansine

Immunoconjugates

Immunologic Factors

Tubulin Modulators

Antimitotic Agents

Folinic Acid

Folate

Vitamin B9

Participants will receive 2 doses of Mirvetuximab Soravtansine after neoadjuvant chemotherapy and before surgical resection of tumor.

Mirvetuximab Soravtansine is a targeted drug for tumors that express high levels of folate receptor alpha.

Mirvetuximab Soravtansine (IMGN853)

Kimberly Blackwell, MD

The main purpose of this study is to determine how 2 doses mirvetuximab soravtansine affects the amount and activity of folate receptor alpha proteins in tumor cells of patients who have completed standard neoadjuvant treatment and are scheduled to have their tumors surgically removed.

The folate receptor alpha protein is important in tumor growth and can be over-expressed in some tumor cells. The word "over-expressed" in this situation means that there are too many copies of the protein on the surface of the cell when compared to a healthy, normal cell, and this helps the tumor continue to grow in size. Mirvetuximab soravtansine acts by targeting the folate receptor in tumor cells. In animal models, mirvetuximab soravtansine is highly effective in decreasing tumor size. This suggests that mirvetuximab soravtansine may help shrink or stop growth of folate receptor alpha positive breast cancer in this study.

In this study the investigator will be looking at how folate receptor alpha expression changes following 2 doses of neoadjuvant mirvetuximab soravtansine. The investigator will also look to evaluate the safety of this regimen, measure any change in tumor size, associate folate receptor alpha expression with a change in tumor size, and describe any changes in Ki-67 and percent of apoptotic cells in this population.

Mirvetuximab Soravtansine (IMG853) in Folate Receptor Alpha-expressing TNBC

Pilot Study of Mirvetuximab Soravtansine (IMGN853) in Folate Receptor Alpha (FRα)-Expressing, Triple Negative Breast Cancer (TNBC) With Residual Disease Post Standard Neoadjuvant Chemotherapy

Assessed by immunohistochemistry (IHC) (1) after completion of neoadjuvant chemotherapy, prior to treatment with mirvetuximab soravtansine; (2) at definitive surgery, after treatment with mirvetuximab soravtansine and scored (0 = no receptors, 1 = small number of receptors, 2 = medium number of receptors, 3 = large number of receptors).

Assessed by immunohistochemistry (IHC) (1) at initial cancer diagnosis, prior to initiation of neoadjuvant chemotherapy; (2) after completion of neoadjuvant chemotherapy and scored (0 = no receptors, 1 = small number of receptors, 2 = medium number of receptors, 3 = large number of receptors).

Assessed by the number of subjects that cannot receive the second dose of mirvetuximab soravtansine

Assessed by the number of subjects that have surgery delayed past 9 weeks due to TEAE

Evaluated by the number of subjects that have either a partial or complete radiologic response by 2D ultrasound. (Partial response = reduction of the largest unidimensional tumor measurement of \>30%; Complete response = no evidence of tumor remaining)

Changes in Ki67 expression will be measured before and after 2 doses of mirvetuximab soravtansine.

Changes in apoptotic markers will be measured before and after 2 doses of mirvetuximab soravtansine.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Evaluating and Monitoring Immune and Clinical Responses in Early-Stage Triple Negative Breast Cancer Undergoing Neoadjuvant Chemo-immunotherapy With Pembrolizumab	NCT05877859	Breast Cancer T... Breast Cancer S... Breast Cancer S... Breast Cancer I...		18 Years -	Emory University
Temozolomide Monotherapy or in Combination With Olaparib in Patients With Triple Negative Breast Cancer (TNBC)	NCT05128734	Breast Cancer T...	Temozolomide Olaparib	18 Years -	AHS Cancer Control Alberta
A Study to Evaluate the Intratumoral Influenza Vaccine Administration in Patients With Breast Cancer	NCT06229392	Breast Cancer Breast Cancer T...	Fluzone Quadriv...	18 Years -	Rush University Medical Center
Neoadjuvant Goserelin for Triple Negative Breast Cancer	NCT03444025	Breast Cancer T...	Goserelin	18 Years - 60 Years	Kasr El Aini Hospital
Mirvetuximab Soravtansine (IMG853) in Folate Receptor Alpha-expressing TNBC	NCT03045393	Breast Cancer T...	Mirvetuximab So...	18 Years -	Duke University
Neoadjuvant Goserelin for Triple Negative Breast Cancer	NCT03444025	Breast Cancer T...	Goserelin	18 Years - 60 Years	Kasr El Aini Hospital
A Study to Evaluate the Intratumoral Influenza Vaccine Administration in Patients With Breast Cancer	NCT06229392	Breast Cancer Breast Cancer T...	Fluzone Quadriv...	18 Years -	Rush University Medical Center

Spots Global Cancer Trial Database for breast cancer triple negative