RGT-419B + Hormonal Therapy for Breast Cancer
Recruiting in Palo Alto (17 mi)
+4 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Regor Pharmaceuticals Inc.
Must be taking: Hormonal therapy
Disqualifiers: Visceral metastases, Pregnancy, others
No Placebo Group
Trial Summary
What is the purpose of this trial?
This trial is testing a new oral drug, RGT-419B, for patients with advanced breast cancer who haven't responded to other treatments. The study aims to see if the drug can safely stop cancer cell growth.
Will I have to stop taking my current medications?
The trial does not specify if you need to stop your current medications, but it mentions that major treatments like chemotherapy or radiation should not have been received within 14-28 days before starting the trial. It's best to discuss your current medications with the trial team.
What data supports the effectiveness of the drug RGT-419B when used with hormonal therapy for breast cancer?
The research highlights that combining hormonal therapy with other agents, like CDK4/6 inhibitors, has improved survival rates in breast cancer patients. This suggests that combining RGT-419B with hormonal therapy might also enhance treatment effectiveness by potentially overcoming resistance to endocrine therapy.12345
What safety data exists for RGT-419B + Hormonal Therapy for Breast Cancer?
The safety of targeted therapies like CDK4/6 inhibitors, which are often combined with hormone therapy for breast cancer, is generally manageable but can include side effects like neutropenia (low white blood cell count) and stomatitis (mouth sores). These side effects require careful management, often involving dose adjustments or additional treatments.678910
How does the drug RGT-419B + Hormonal Therapy differ from other breast cancer treatments?
RGT-419B + Hormonal Therapy is unique because it combines a novel drug, RGT-419B, with hormonal therapy, potentially offering a new mechanism of action or enhanced effectiveness compared to existing treatments like tamoxifen or aminoglutethimide alone. This combination may provide a more comprehensive approach by targeting different pathways involved in breast cancer progression.1112131415
Eligibility Criteria
This trial is for adults with HR+, HER2- advanced or metastatic breast cancer who've had no more than one prior chemotherapy in this setting and less than three lines of CDK4/6i therapy. Participants must have an ECOG Performance Status of 0 to 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory.Inclusion Criteria
My tumor is HR positive, HER2 negative, and can be measured.
I've had only one chemotherapy for advanced breast cancer, tolerated CDK4/6 inhibitors well, can take RT-419B, and recovered from past therapy side effects.
I have advanced breast cancer, tried <3 CDK4/6i therapies, and no more than 1 chemotherapy.
See 3 more
Exclusion Criteria
My cancer has spread to my organs, causing severe problems.
I haven't had major surgery or cancer treatment in the last 14 days.
I have not had radiation to more than a quarter of my bone marrow and my organs are functioning well.
See 3 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive RGT-419B as monotherapy or in combination with Hormonal Therapy to evaluate safety, tolerability, and pharmacokinetics
4 weeks (1 cycle)
Multiple visits for dose administration and monitoring
Follow-up
Participants are monitored for safety, tolerability, and efficacy through study completion
up to 1 year
Treatment Details
Interventions
- RGT-419B (Small Molecule Inhibitor)
Trial OverviewThe study tests RGT-419B, a new oral medication, alone or combined with hormonal therapy. It's a phase I trial focusing on safety, how the body processes the drug (pharmacokinetics), and its initial effectiveness against certain types of breast cancer that progressed after previous treatments.
Participant Groups
2Treatment groups
Experimental Treatment
Group I: Arm BExperimental Treatment1 Intervention
RGT-419B in combination with Hormonal Therapy
Group II: Arm AExperimental Treatment1 Intervention
RGT-419B given alone as monotherapy
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Hem-Onc Associates of the Treasure CoastPort Saint Lucie, FL
Emory UniversityAtlanta, GA
Massachusetts General HospitalBoston, MA
New York Cancer and Blood SpecialistsPort Jefferson Station, NY
More Trial Locations
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Who Is Running the Clinical Trial?
Regor Pharmaceuticals Inc.Lead Sponsor
References
Breast cancer: current and future endocrine therapies. [2018]Endocrine therapy forms a central modality in the treatment of estrogen receptor positive breast cancer. The routine use of 5 years of adjuvant tamoxifen has improved survival rates for early breast cancer, and more recently has evolved in the postmenopausal setting to include aromatase inhibitors. The optimal duration of adjuvant endocrine therapy remains an active area of clinical study with recent data supporting 10 years rather than 5 years of adjuvant tamoxifen. However, endocrine therapy is limited by the development of resistance, this can occur by a number of possible mechanisms and numerous studies have been performed which combine endocrine therapy with agents that modulate these mechanisms with the aim of preventing or delaying the emergence of resistance. Recent trial data regarding the combination of the mammalian target of rapamycin (mTOR) inhibitor, everolimus with endocrine therapy have resulted in a redefinition of the clinical treatment pathway in the metastatic setting. This review details the current endocrine therapy utilized in both early and advanced disease, as well as exploring potential new targets which modulate pathways of resistance, as well as agents which aim to modulate adrenal derived steroidogenic hormones.
Ribociclib plus fulvestrant in the treatment of breast cancer. [2021]Endocrine therapy (ET) is a standard first-line treatment for hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC) Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have demonstrated significantly improved progression-free survival (PFS) with ET in patients with ABC. Recent reports indicate that the addition of the CDK4/6i ribociclib to ET, including fulvestrant, significantly improves PFS and overall survival (OS).
Overcoming endocrine resistance in metastatic hormone receptor-positive breast cancer. [2019]Endocrine therapy has historically formed the basis of treatment of metastatic hormone receptor-positive breast cancer. The development of endocrine resistance has led to the development of newer endocrine drug combinations. Use of the CDK4/6 inhibitors has significantly improved progression-free survival in this group of patients. There are multiple studies of the use of P13K inhibitors and mTOR inhibitors for use as subsequent lines of therapy, particularly for endocrine resistance. The optimal sequencing of therapy should be based on medical comorbidities, prior adjuvant therapies, quality of life, side-effect profile, and disease-free interval.
Update on endocrine therapy for breast cancer. [2006]The choice of endocrine agent for breast cancer depends on the menopausal status of the patient, the stage of disease, prognostic factors, and the toxicity profile of the agent. Endocrine therapies are typically given sequentially, with the least toxic therapy given first. Tamoxifen is considered first-line endocrine therapy for all stages of breast cancer. New antiestrogens in development include nonsteroidal agents related to tamoxifen and pure steroidal antiestrogens. Luteinizing hormone-releasing hormone agonists are an effective form of endocrine therapy for premenopausal women with advanced breast cancer, and aromatase inhibitors are effective in postmenopausal women. Newer and more selective aromatase inhibitors that are p.o. active and have improved side-effect profiles have been developed. Recent trials have found these agents to improve survival in comparison to the progestins; thus, aromatase inhibitors are replacing progestins as second-line therapy for metastatic disease. Current trials are examining the potential role of aromatase inhibitors as first-line therapy for metastatic disease or as adjuvant therapy for early disease. The antiprogestins and antiandrogens studied thus far have had only limited success in breast cancer clinical trials.
Endocrine therapy in post-menopausal women with metastatic breast cancer: From literature and guidelines to clinical practice. [2018]Current international guidelines recommend endocrine therapy as the initial treatment of choice in hormone receptor positive advanced breast cancer. Endocrine therapy has been a mainstay of hormone responsive breast cancer treatment for more than a century. To date it is based on different approaches,such as blocking the estrogen receptor through selective receptor estrogen modulators, depleting extragonadal peripheral estrogen synthesis by aromatase inhibitors or inducing estrogen receptor degradation using selective down-regulators. Despite estrogen and/or progesterone receptor positive status, up to a quarter of patients could be either primarily resistant to hormone therapies or will develop hormone resistance during the course of their disease. Different mechanisms, either intrinsic or acquired, could be implicated in endocrine resistance. In the present work available endocrine therapies and their appropriate sequences have been reviewed, and the most promising strategies to overcome endocrine resistance have been highlighted.
Molecularly targeted therapy and immunotherapy for hormone receptor‑positive/human epidermal growth factor receptor 2‑negative advanced breast cancer (Review). [2021]The advent of targeted therapy for hormone receptor‑positive/human epidermal growth factor receptor 2‑negative advanced breast cancer (HR+/HER2‑ aBC) provides a novel therapeutic approach other than endocrine therapy. One targeted signaling pathway and three immune‑checkpoints have been demonstrated to be in association with tumor proliferation and growth in HR+/HER2‑ aBC. A number of phosphoinositide 3‑kinase/AKT/mammalian target of rapamycin signaling pathway inhibitors demonstrate clinical activity against this tumor subtype. The CDK4/6 inhibitors as a single agent or in combination with endocrine therapy have produced promising tumor response with acceptable toxicity in patients with HR+/HER2‑ aBC. Programmed death 1/programmed death ligand 1 (PD1/PD‑L1) and cytotoxic T lymphocyte antigen‑4 inhibitors can also produce an antitumor immune response, which provides a proof‑of‑principle for the initial utilization of immunotherapy in breast cancer. The aim of the present review was to discuss the mechanisms of action, clinical efficacy and safety profiles of all the targeted biological therapies and immunotherapies that have been approved or are currently under evaluation for HR+/HER2‑ aBC.
Improving Response to Hormone Therapy in Breast Cancer: New Targets, New Therapeutic Options. [2022]The majority of breast cancer expresses the estrogen and or progesterone receptors (ER and PR). In tumors without concomitant HER2 amplification, hormone therapy is a major treatment option for all disease stages. Resistance to hormonal therapy is associated with disease recurrence and progression. Recent studies have identified a number of resistance mechanisms leading to estrogen-independent growth of hormone receptor-positive (HR+) breast cancer as a result of genetic and epigenetic alterations, which could be exploited as novel therapeutic targets. These include acquired mutations in ER-alpha (ESR1) in response to endocrine deprivation; constitutive activation of cyclin-dependent kinases (CDK) 4 and 6; cross talk between ER and growth factor receptor signaling such as HER family members, fibroblast growth factor receptor (FGFR) pathways, intracellular growth, and survival signals PI3K/Akt/mTOR; and epigenetic modifications by histone deacetylase (HDAC) as well as interactions with tumor microenvironment and host immune response. Inhibitors of these pathways are being developed to improve efficacy of hormonal therapy for treatment of both metastatic and early-stage disease. Two agents are currently approved in the United States for the treatment of metastatic HR+ breast cancer, including the mTOR inhibitor everolimus and the CDK4/6 inhibitor palbociclib. Management of toxicity is a critical aspect of treatment; the primary toxicity of everolimus is stomatitis (treated with topical steroids) and of palbociclib is neutropenia (treated with dose reduction/delay). Many agents are in clinical trials, primarily in combination with hormone therapy; novel combinations are under active investigation.
Management of toxicities associated with targeted therapies for HR-positive metastatic breast cancer: a multidisciplinary approach is the key to success. [2020]Agents targeting HR-positive, HER2-negative locally advanced or metastatic breast cancer have improved patient outcomes compared with conventional single-agent endocrine therapy. Currently, approved targeted agents include everolimus and three CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib. Unlike the well-characterized and easily manageable safety profile of endocrine therapies, adverse events associated with targeted therapies are complex and potentially severe. Their prompt recognition and treatment, crucial for prolonged endocrine sensitivity and survival, may be challenging and requires a multidisciplinary effort and a good knowledge of drug interactions.
Survival outcomes after neoadjuvant letrozole and palbociclib versus third generation chemotherapy for patients with high-risk oestrogen receptor-positive HER2-negative breast cancer. [2022]Besides their development as additional adjuvant treatments, CDK4/6 inhibitors combined with endocrine therapy could represent less toxic alternatives to chemotherapy in postmenopausal women with high-risk oestrogen receptor-positive, HER2-negative breast cancer currently a candidate for chemotherapy. The multicentre, international, randomised phase 2 NEOPAL trial showed that the letrozole-palbociclib combination led to clinical and pathological responses equivalent to sequential anthracycline-taxanes chemotherapy. Secondary objectives included survival outcomes.
Abiraterone shows alternate activity in models of endocrine resistant and sensitive disease. [2022]Resistance to endocrine therapy remains a major clinical problem in the treatment of oestrogen-receptor positive (ER+) breast cancer. Studies show androgen-receptor (AR) remains present in 80-90% of metastatic breast cancers providing support for blockade of AR-signalling. However, clinical studies with abiraterone, which blocks cytochrome P450 17A1 (CYP17A1) showed limited benefit.
Treatment of advanced breast cancer with aminoglutethimide--response after previous tamoxifen treatment. [2014]Thirty-one postmenopausal patients with advanced breast cancer either unresponsive to tamoxifen or progressing after responding to tamoxifen were treated with aminoglutethimide (1 000 - 1 250 mg/d) plus hydrocortisone replacement. The response rate was 33% in patients who had never responded to tamoxifen and 47% in patients who had previously responded to tamoxifen. The overall response rate was 42%. These results show that aminoglutethimide is an effective second-line hormonal treatment for patients with advanced breast cancer.
[Hormone therapy of breast cancer in the metastatic phase in menopausal women]. [2016]Hormone therapy for breast cancer was initially used before menopause due to the castration effect but rapidly was extended to menopaused women. Over the last 20 years, two major types of hormone therapy have been developed, those based on surgical removal of the adrenal or pituitary glands and medical treatment with estrogens and androgens. There are currently 3 major classes of medical hormone therapies. Antiestrogens can provide objective remission in about one-third of the patients. These drugs block the estrogen receptors. Progestins can also be effective in about 40% of the patients. The third class currently includes two aromatase inhibitors, aminoglutethimide and 4 OH androstenedione. These drugs block estrogen and estradiol secretion in the ovaries and adrenal glands. Combination therapies have also been used in an attempt to take advantage of the different mechanisms of action. Others have added chemotherapy, attempting to optimize the chronology of these two complementary treatments. In case of relapse after an initial treatment, second line hormonotherapy can again be used, with objective response varying from 32 to 46% in patients who had responded to the initial treatment.
The influence of aminoglutethimide and its analogue rogletimide on peripheral aromatisation in breast cancer. [2019]The influence of the prototype aromatase inhibitor Aminoglutethimide (AG) and its analogue Rogletimide (RG) on peripheral aromatisation were investigated in 13 postmenopausal women with advanced breast cancer. Seven patients received AG 1,000 mg daily plus Hydrocortisone (HC) cover and six received RG as dose escalation of 200 mg bd, 400 mg bd and 800 mg bd. In vivo aromatase inhibition was investigated using the double bolus injection technique with [4-14C] oestrone ([4-14C]E1) and [6,7-3H] androstenedione ([6,7-3H]4A) followed by a 96 h urine collection. The labelled urinary oestrogens were separated and purified by chromatography and HPLC. Plasma oestradiol (E2) was also measured. AG mean aromatase inhibition was 90.6% +/- 1.8 s.e.m. and E2 suppression 75.7% +/- 7.3 s.e.m. RG mean aromatase inhibition was 50.6% +/- 9.8 s.e.m. at 200 mg bd, 63.5% +/- 5.7 s.e.m. at 400 mg bd and 73.8% +/- 5.8 s.e.m. at 800 mg bd. E2 suppression was 30.7% +/- 9.5 s.e.m., 40.2% +/- 10.3 s.e.m. and 57.6% +/- 9.2 s.e.m. respectively. These results confirm the efficacy of AG as an aromatase inhibitor. RG produced dose dependent E2 suppression and aromatase inhibition, but even at the maximum tolerated dose of 800 mg bd had sub-optimal aromatase inhibition and oestradiol suppression compared with AG.
[Experimental multihormone therapy on human breast carcinomas grown in nude mice]. [2013]Experimental multihormone therapy with tamoxifen (TAM), aminoglutethimide (AMG) and medroxyprogesterone acetate (MPA) was investigated using three hormone-dependent human breast carcinomas serially transplanted into nude mice. TAM was the most effective of these agents, showing an efficacy rate of 100%, whereas MPA was the least effective, showing an efficacy rate of only 17%. The combination treatment of TAM and AMG was more effective than that of either TAM or AMG used alone. The antitumor effect of TAM was considered to be related to the changes of the hormone receptor levels. Since AMG significantly reduced the estrogen level and the uterine weight in normal female mice, the antitumor effect of combined TAM and AMG was assumed to be a result of the low estrogen level caused by AMG, enhancing the ability of TAM to compete with estrogen receptors. There was no additional antitumor effect of the combination of TAM and MPA, although serum MPA levels in mice were almost equivalent to those in humans who were treated with 1200mg of MPA po daily. These results indicated that combination hormone therapy, particularly with TAM and AMG, might be a promising method for the clinical treatment of human breast cancer.
Response to aminoglutethimide after tamoxifen therapy in advanced breast cancer. [2021]We describe sequential response to aminoglutethimide after eventual failure of treatment with tamoxifen in a patient with metastatic breast cancer. We suggest that aminoglutethimide is the next logical hormone therapy for such patients.