TROP2 ADC for Cancer (A264 Trial)
Palo Alto (17 mi)Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: Klus Pharma Inc.
No Placebo Group
Approved in 3 jurisdictions
Trial Summary
What is the purpose of this trial?A Phase I-II, First-in-Human Study of SKB264 in Patients with Locally Advanced Unresectable/Metastatic Solid Tumors who are refractory to Available Standard Therapies. Patient must have historically documented, incurable, locally advanced or metastatic cancer that are refractory to standard therapies of one of the following types:
1. Triple negative breast cancer
2. Epithelial ovarian cancer
3. Non-small cell lung cancer
4. Gastric adenocarcinoma/Gastroesophageal junction adenocarcinoma
5. Small cell lung cancer
6. HR+/ HER2-breast cancer
7. Head and neck squamous cell carcinoma
8. Endometrial carcinoma
9. Urothelial carcinoma
Do I have to stop taking my current medications for the TROP2 ADC cancer trial?The trial protocol does not specify if you must stop taking your current medications. However, you cannot use strong inhibitors or inducers of CYP3A4 at least 14 days before and throughout the study. Also, any standard cancer therapy or experimental therapy must be stopped at least 4 weeks or 5 half-lives before the first infusion of the study drug.
Is the drug SKB264 (also known as MK-2870) a promising treatment for cancer?Yes, SKB264 is a promising treatment for cancer because it targets Trop-2, a protein that is overexpressed in many cancer cells. This makes it a good target for therapies, and Trop-2-targeted drugs have shown strong anti-cancer effects in clinical trials. These drugs can also work well with other cancer treatments, potentially improving their effectiveness.2581315
What safety data is available for TROP2 ADC (SKB264, MK-2870) in cancer treatment?The provided research does not contain specific safety data for TROP2 ADC (SKB264, MK-2870) in cancer treatment. The studies focus on other agents and the role of TROP2 in prostate cancer, but do not provide safety data for the specific treatment in question.134714
What data supports the idea that TROP2 ADC for Cancer (also known as: SKB264, MK-2870) is an effective treatment?The available research does not provide specific data on the effectiveness of TROP2 ADC for Cancer (SKB264, MK-2870). Instead, it focuses on other treatments like entrectinib and AZD4547, which target different genetic fusions in cancer. These studies show that entrectinib can reduce tumor size in colorectal cancer and AZD4547 can delay tumor growth in certain cancer models. However, there is no direct information on TROP2 ADC for Cancer in the provided research.69101112
Eligibility Criteria
Adults aged 18-75 with advanced solid tumors that can't be surgically removed or have spread and don't respond to standard treatments. Specific cancers include certain types of breast, ovarian, lung, gastric, head and neck, endometrial, and urothelial cancers. Participants must have acceptable organ function and blood counts, not require oxygen for daily activities or have severe heart conditions.Inclusion Criteria
I am fully active or can carry out light work.
My kidneys work well enough to clear waste from my blood.
My cancer is advanced, cannot be cured, and started in the lining of organs.
I am between 18 and 75 years old.
Exclusion Criteria
I have been treated with TROP 2 targeted therapies before.
I have a serious heart condition that needs treatment.
I haven't had cancer treatment in the last 4 weeks or before the study drug's half-life period.
I need extra oxygen to do my daily activities.
I haven't had major surgery in the last 4 weeks.
I have high blood pressure or diabetes that is not well-managed.
I have severe eye conditions like dry eye, Meibomian gland disease, or macular degeneration.
I have fluid buildup in my chest causing symptoms.
I have moderate to severe numbness, tingling, or pain in my hands or feet.
I have had lung conditions that needed steroids or caused severe breathing problems.
I have or had liver disease, including hepatitis, alcoholism, or cirrhosis.
I need a procedure to remove excess fluid from my abdomen.
Treatment Details
SKB264 is being tested in this Phase I-II trial on patients with various advanced solid tumors unresponsive to standard therapies. The study aims to evaluate the safety and effectiveness of SKB264 as a potential treatment option for these patients.
11Treatment groups
Experimental Treatment
Group I: Phase II: Urothelial carcinomaExperimental Treatment1 Intervention
Histologically or cytologically documented, incurable, locally advanced or metastatic cancer
Group II: Phase II: Triple Negative Breast CancerExperimental Treatment1 Intervention
Histologically documented or cytologically , incurable, locally advanced or metastatic cancer
Group III: Phase II: Non-Small Cell Lung CancerExperimental Treatment1 Intervention
Histologically documented or cytologically, incurable, locally advanced or metastatic cancer
Group IV: Phase II: Head and Neck Squamous Cell CarcinomaExperimental Treatment1 Intervention
Histologically documented or cytologically, incurable, locally advanced or metastatic cancer
Group V: Phase II: HR+/ HER2- Breast CancerExperimental Treatment1 Intervention
Histologically documented or cytologically, incurable, locally advanced or metastatic cancer
Group VI: Phase II: Gastric Adenocarcinoma or Gastroesophageal Junction AdenocarcinomaExperimental Treatment1 Intervention
Histologically or cytologically documented, incurable, locally advanced or metastatic cancer
Group VII: Phase II: Extensive-stage Small Cell Lung CancerExperimental Treatment1 Intervention
Histologically documented or cytologically, incurable, locally advanced or metastatic cancer
Group VIII: Phase II: Epithelial Ovarian CancerExperimental Treatment1 Intervention
Histologically documented or cytologically, incurable, locally advanced or metastatic cancer
Group IX: Phase II: Endometrial carcinomaExperimental Treatment1 Intervention
Histologically documented or cytologically, incurable, locally advanced or metastatic cancer
Group X: Phase II: Cervical CancerExperimental Treatment1 Intervention
Histologically or cytologically documented, incurable, locally advanced or metastatic cancer
Group XI: Phase I: Dose EscalationExperimental Treatment1 Intervention
Five dose levels have been selected for evaluation in the Phase I part of the study: 2, 4, 6, 9, and 12 mg/kg of SKB264
SKB264 is already approved in China, European Union, United States for the following indications:
🇨🇳 Approved in China as SKB264 for:
- Triple-negative breast cancer
- EGFR-mutated non-small cell lung cancer
🇪🇺 Approved in European Union as SKB264 for:
- Clinical trials approved but no specific indications listed yet
🇺🇸 Approved in United States as SKB264 for:
- Clinical trials ongoing but no specific indications approved yet
Find a clinic near you
Research locations nearbySelect from list below to view details:
Los Angeles Hematology Oncology Medical GroupGlendale, CA
Florida Cancer Specialists & Research InstituteLake Mary, FL
BRCR Medical Center, IncPlantation, FL
Willis-Knighton Medical CenterShreveport, LA
More Trial Locations
Loading ...
Who is running the clinical trial?
Klus Pharma Inc.Lead Sponsor
References
A phase IB study of ABT-751 in combination with docetaxel in patients with advanced castration-resistant prostate cancer. [2020]This study investigated the safety, pharmacokinetics (PK) and clinical antitumor activity of ABT-751, a novel sulfonamide antimitotic and vascular disrupting agent, in combination with docetaxel (Taxotere) in patients with castration-resistant prostate cancer (CRPC).
[Expression and clinical significance of Trop-2 in human pancreatic cancer]. [2011]To investigate the expression and its clinical significance of Trop-2 in human pancreatic cancer.
Novel agents in the management of castration resistant prostate cancer. [2022]Prostate cancer (PCa) is a leading cause of cancer mortality in men and despite high cure rates with surgery and/or radiation, 30-40% of patients will eventually develop advanced disease. Androgen deprivation is the first line therapy for standard of care for men with advanced disease. Eventually however all men will progress to castration-resistant prostate cancer (CRPC). Insight into the molecular mechanisms of androgen resistance has led to the development of alternative novel hormonal agents. Newer hormonal agents such as abiraterone, enzalutamide and TOK-001; and the first cancer vaccine, Sipuleucel T have been approved for use in men with CRPC. The recognition of the importance of bone health and morbidity associated with skeletal related events has led to the introduction of the receptor activator of nuclear factor kappa-B-ligand inhibitor denosumab. Other molecularly targeted therapies have shown promise in pre-clinical studies, but this has not consistently translated into clinical efficacy. It is increasingly evident that CRPC is a heterogeneous disease and an individualized approach directed at identifying primary involvement of specific pathways could maximize the benefit from targeted therapies. This review focuses on targeted therapy for PCa with special emphasis on therapies that have been Food and Drug Administration approved for use in men with CRPC.
Phase I Study of CKD-516, a Novel Vascular Disrupting Agent, in Patients with Advanced Solid Tumors. [2018]CKD-516 is a newly developed vascular disrupting agent. This phase I dose-escalation study of CKD-516 was conducted to determine maximum-tolerated dose (MTD), safety, pharmacokinetics, and preliminary antitumor efficacy in patients with advanced solid tumors.
Trop2 and its overexpression in cancers: regulation and clinical/therapeutic implications. [2022]Trop2 is a transmembrane glycoprotein encoded by the Tacstd2 gene. It is an intracellular calcium signal transducer that is differentially expressed in many cancers. It signals cells for self-renewal, proliferation, invasion, and survival. It has stem cell-like qualities. Trop2 is expressed in many normal tissues, though in contrast, it is overexpressed in many cancers and the overexpression of Trop2 is of prognostic significance. Several ligands have been proposed that interact with Trop2. Trop2 signals the cells via different pathways and it is transcriptionally regulated by a complex network of several transcription factors. Trop2 expression in cancer cells has been correlated with drug resistance. Several strategies target Trop2 on cancer cells that include antibodies, antibody fusion proteins, chemical inhibitors, nanoparticles, etc. The in vitro studies and pre-clinical studies, using these various therapeutic treatments, have resulted in significant inhibition of tumor cell growth both in vitro and in vivo in mice. A clinical study is underway using IMMU-132 (hrS7 linked to SN38) in patients with epithelial cancers. This review describes briefly the various characteristics of cancer cells overexpressing Trop2 and the potential application of Trop2 as both a prognostic biomarker and as a therapeutic target to reverse resistance.
Sensitivity to Entrectinib Associated With a Novel LMNA-NTRK1 Gene Fusion in Metastatic Colorectal Cancer. [2018]In metastatic colorectal cancer (CRC), actionable genetic lesions represent potential clinical opportunities. NTRK1, 2, and 3 gene rearrangements encode oncogenic fusions of the tropomyosin-receptor kinase (TRK) family of receptor tyrosine kinases in different tumor types. The TPM3-NTRK1 rearrangement is a recurring event in CRC that renders tumors sensitive to TRKA kinase inhibitors in preclinical models. We identified abnormal expression of the TRKA protein in tumor and liver metastases of a CRC patient refractory to standard therapy. Molecular characterization unveiled a novel LMNA-NTRK1 rearrangement within chromosome 1 with oncogenic potential, and the patient was treated with the pan-TRK inhibitor entrectinib, achieving partial response with decrease in hepatic target lesions from 6.8 and 8.2cm in longest diameter to 4.7 and 4.3cm, respectively. To our knowledge, this is the first clinical evidence of efficacy for therapeutic inhibition of TRKA in a solid tumor, illuminating a genomic-driven strategy to identify CRCs reliant on this oncogene to be clinically targeted with entrectinib.
High expression of TROP2 characterizes different cell subpopulations in androgen-sensitive and androgen-independent prostate cancer cells. [2018]Progression of castration-resistant tumors is frequent in prostate cancer. Current systemic treatments for castration-resistant prostate cancer only produce modest increases in survival time and self-renewing Tumor-Initiating Cells (TICs) are suspected to play an important role in resistance to these treatments. However it remains unclear whether the same TICs display both chemo-resistance and self-renewing abilities throughout progression from early stage lesions to late, castration resistant tumors. Here, we found that treatment of mice bearing LNCaP-derived xenograft tumors with cytotoxic (docetaxel) and anti-androgen (flutamide) compounds enriched for cells that express TROP2, a putative TIC marker. Consistent with a tumor-initiating role, TROP2high cells from androgen-sensitive prostate cancer cell lines displayed an enhanced ability to re-grow in culture following treatment with taxane-based chemotherapy with or without androgen blockade. TROP2 down-regulation in these cells reduced their ability to recur after treatment with docetaxel, in the presence or absence of flutamide. Accordingly, in silico analysis of published clinical data revealed that prostate cancer patients with poor prognosis exhibit significantly elevated TROP2 expression level compared to low-risk patients, particularly in the case of patients diagnosed with early stage tumors. In contrast, in androgen-independent prostate cancer cell lines, TROP2high cells did not exhibit a differential treatment response but were characterized by their high self-renewal ability. Based on these findings we propose that high TROP2 expression identifies distinct cell sub-populations in androgen-sensitive and androgen-independent prostate tumors and that it may be a predictive biomarker for prostate cancer treatment response in androgen-sensitive tumors.
Targeting Trop-2 in solid tumors: future prospects. [2023]Trop-2 is a transmembrane glycoprotein that is upregulated in all cancer types independent of baseline levels of Trop-2 expression. Trop-2 is an ideal candidate for targeted therapeutics due to it being a transmembrane protein with an extracellular domain overexpressed on a wide variety of tumors as well as its upregulated expression relative to normal cells. As a result, several Trop-2-targeted therapeutics have recently been developed for clinical use, such as anti-Trop-2 antibodies and Trop-2-targeted antibody-drug conjugates (ADC). Subsequently, multiple early-phase clinical trials have demonstrated safety and clinical benefit of Trop-2-based ADCs across multiple tumor types. This includes clinical benefit and tolerability in tumor types with limited treatment options, such as triple-negative breast cancer, platinum-resistant urothelial cancer, and small-cell lung cancer. In this review, we elaborate on all clinical trials involving Trop-2.
Nerve Growth Factor Induces Proliferation and Aggressiveness In Prostate Cancer Cells. [2023]Resistance to hormone therapy and disease progression is the major challenge in clinical management of prostate cancer (PC). Drugs currently used in PC therapy initially show a potent antitumor effects, but PC gradually develops resistance, relapses and spreads. Most patients who fail primary therapy and have recurrences eventually develop castration-resistant prostate cancer (CRPC), which is almost incurable. The nerve growth factor (NGF) acts on a variety of non-neuronal cells by activating the NGF tyrosine-kinase receptor, tropomyosin receptor kinase A (TrkA). NGF signaling is deregulated in PC. In androgen-dependent PC cells, TrkA mediates the proliferative action of NGF through its crosstalk with the androgen receptor (AR). Epithelial PC cells, however, acquire the ability to express NGF and TrkA, as the disease progresses, indicating a role for NGF/TrkA axis in PC progression and androgen-resistance. We here report that once activated by NGF, TrkA mediates proliferation, invasiveness and epithelial-mesenchymal transition (EMT) in various CRPC cells. NGF promotes organoid growth in 3D models of CRPC cells, and specific inhibition of TrkA impairs all these responses. Thus TrkA represents a new biomarker to target in CRPC.
Pharmacokinetic-Pharmacodynamic-Efficacy Modeling of ONO-7579, a Novel Pan-Tropomyosin Receptor Kinase Inhibitor, in a Murine Xenograft Tumor Model. [2020]The orally available and novel small molecule ONO-7579 (N-{2-[4-(2-amino-5-chloropyridin-3-yl)phenoxy]pyrimidin-5-yl}-N'-[2-(methanesulfonyl)-5-(trifluoromethyl)phenyl]urea) is a highly potent and selective pan-tropomyosin receptor kinase (TRK) inhibitor. The objective of the present study was to characterize the pharmacokinetic (PK), pharmacodynamic (PD), and antitumor efficacy relationships of ONO-7579 in mice xenografted with a human colorectal cancer cell line, KM12 (harboring the tropomyosin 3 (TPM3) -neurotrophic tyrosine receptor kinase 1 fusion gene), via a PK/PD modeling approach. Plasma and tumor concentrations of ONO-7579, tumor levels of phosphorylated TPM3-TRKA (pTRKA), and tumor volumes in the murine model were measured with a single or multiple dose of ONO-7579 (0.06-0.60 mg/kg) administered once daily. The PK/PD/efficacy models were developed in a sequential manner. Changes in plasma concentrations of ONO-7579 were described with an oral one-compartment model. Tumor concentrations of ONO-7579 were higher than plasma concentrations, and changes in ONO-7579 tumor concentrations were described with an additional tumor compartment that had no influence on plasma concentrations. pTRKA in tumors was described with a direct Emax model, and the tumor ONO-7579 concentration causing 50% of the maximum effect was estimated to be 17.6 ng/g. In addition, a pTRKA-driven tumor growth inhibition model indicated that ONO-7579 started to sharply increase the antitumor effect at pTRKA inhibition rates >60% and required >91.5% to reduce tumors. In conclusion, the developed PK/PD/efficacy models revealed a "switch-like" relationship between pTRKA inhibition rate and antitumor effect in a murine KM12 xenograft model, demonstrating that pTRKA in tumors could serve as an effective biomarker for scheduling the dose regimen in early-stage clinical studies. SIGNIFICANCE STATEMENT: In recent years, clinical development of TRK inhibitors in patients with neurotrophic tyrosine receptor kinase fusion-positive solid tumors has been accelerated. This research found that phosphorylated TRKA was a useful biomarker for explaining the antitumor efficacy of TRK inhibitors using a pharmacokinetic/pharmacodynamic modeling approach in xenograft mice. This finding suggests a rational dosing regimen in early-stage clinical studies for ONO-7579 (N-{2-[4-(2-amino-5-chloropyridin-3-yl)phenoxy]pyrimidin-5-yl}-N'-[2-(methanesulfonyl)-5-(trifluoromethyl)phenyl]urea), a novel pan-TRK inhibitor.
Inhibition of MEK1/2 Forestalls the Onset of Acquired Resistance to Entrectinib in Multiple Models of NTRK1-Driven Cancer. [2023]NTRK1 gene fusions are actionable drivers of numerous human malignancies. Here, we show that expression of the TPR-NTRK1 fusion kinase in immortalized mouse pancreatic ductal epithelial (IMPE) (pancreas) or mouse lung epithelial (MLE-12) cells is sufficient to promote rapidly growing tumors in mice. Both tumor models are exquisitely sensitive to targeted inhibition with entrectinib, a tropomyosin-related kinase A (TRKA) inhibitor. Initial regression of NTRK1-driven tumors is driven by induced expression of BIM, such that BIM silencing leads to a diminished response to entrectinib in vivo. However, the emergence of drug-resistant disease limits the long-term durability of responses. Based on the reactivation of RAF>MEK>ERK signaling observed in entrectinib-treated tumors, we show that the combination of entrectinib plus the MEK1/2 inhibitor cobimetinib dramatically forestalls the onset of drug resistance in vivo. Collectively, these data provide a mechanistic rationale for rapid clinical deployment of combined inhibition of TRKA plus MEK1/2 in NTRK1-driven cancers.
Anti-Tumor Activity of AZD4547 Against NTRK1 Fusion Positive Cancer Cells Through Inhibition of NTRKs. [2021]Inhibitors of tropomyosin-related kinases (TRKs) display remarkable outcomes in the regression of cancers harboring the Neurotrophin Receptors Tyrosine Kinase (NTRK) fusion gene. As a result, TRKs have become attractive targets in anti-cancer drug discovery programs. Here, we demonstrate that AZD4547, a highly potent and selective inhibitor of fibroblast growth factor receptor (FGFR), displays anti-tumor activity against KM12(Luc) harboring the TPM3-NTRK1 fusion gene associated with its direct inhibition of TRKs. The results of profiling, using a 64-member in-house cancer cell panel, show that AZD4547 displays anti-proliferation activity against KM12(Luc) with a GI50 of 100 nM. In vitro biochemical assays reveal that AZD4547 has IC50 values of 18.7, 22.6 and 2.9 nM against TRKA, B and C, respectively. In a cellular context, AZD4547 blocks auto-phosphorylation of TRKs and phosphorylation of its downstream molecules including PLC-gamma and AKT in a dose dependent manner. Also, AZD4547 at 0.1 μM concentration downregulates expression of MAPK target genes (DUSP6, CCND1 and ETV1) as well as the E2F pathway. Furthermore, AZD4547 induces G0/G1 arrest and apoptosis, and suppresses anchorage independent growth of KM12(Luc). Oral administration of 40 mpk AZD4547 dramatically delays tumor growth in a KM12(Luc) implemented xenograft model, without promoting body weight changes. The capability of AZD4547 to inhibit TRKA, TRKB and clinically relevant mutants (TRKA G595R, G667S, G667C and G667A) was also evaluated using Ba/F3 cells harboring the ETV6-NTRKs fusion gene. The combined observations demonstrate the potential application of AZD4547 for treatment of NTRK fusion driven cancers.
Advances in Trop2-targeted therapy: Novel agents and opportunities beyond breast cancer. [2023]Trop2 is a transmembrane glycoprotein and calcium signal transducer with limited expression in normal human tissues. It is consistently overexpressed in a variety of malignant tumors and participates in several oncogenic signaling pathways that lead to tumor development, invasion, and metastasis. As a result, Trop2 has become an attractive therapeutic target in cancer treatment. The anti-Trop2 antibody-drug conjugate (Trodelvy™, sacituzumab govitecan) has been approved to treat metastatic triple-negative breast cancer. However, it is still unclear whether the success observed in Trop2-positive breast cancer could be replicated in other tumor types, owing to the differences in the expression levels and functions of Trop2 across cancer types. In this review, we summarize the recent progress on the structures and functions of Trop2 and highlight the potential diagnostic and therapeutic value of Trop2 beyond breast cancer. In addition, the promising novel Trop2-targeted agents in the clinic were discussed, which will likely alter the therapeutic landscape of Trop2-positive tumors in the future.
Expression and Therapeutic Targeting of TROP-2 in Treatment-Resistant Prostate Cancer. [2023]Men with metastatic castration-resistant prostate cancer (mCRPC) frequently develop resistance to androgen receptor signaling inhibitor (ARSI) treatment; therefore, new therapies are needed. Trophoblastic cell-surface antigen (TROP-2) is a transmembrane protein identified in prostate cancer and overexpressed in multiple malignancies. TROP-2 is a therapeutic target for antibody-drug conjugates (ADC).
Targeting Trop-2 in cancer: Recent research progress and clinical application. [2023]The development of new antitumor drugs depends mainly upon targeting tumor cells precisely. Trophoblast surface antigen 2 (Trop-2) is a type I transmembrane glycoprotein involved in Ca2+ signaling in tumor cells. It is highly expressed in various tumor tissues than in normal tissues and represents a novel and promising molecular target for caner targeted therapy. Up to now, the mechanisms and functions associated with Trop-2 have been extensively studied in a variety of solid tumors. According to these findings, Trop-2 plays an important role in cell proliferation, apoptosis, cell adhesion, epithelial-mesenchymal transition, as well as tumorigenesis and tumor progression. In addition, Trop-2 related drugs are also being developed widely. There are a number of Trop-2 related ADC drugs that have demonstrated potent antitumor activity and are currently been studied, such as Sacituzumab Govitecan (SG) and Datopotamab Deruxtecan (Dato-Dxd). In this study, we reviewed the progress of Trop-2 research in solid tumors. We also sorted out the composition and rationale of Trop-2 related drugs and summarized the related clinical trials. Finally, we discussed the current status of Trop-2 research and expanded our perspectives on its future research directions. Importantly, we found that Trop-2 targeted ADCs have great potential for combination with other antitumor therapies. Trop-2 targeted ADCs can reprogramme tumor microenvironment through multiple signaling pathways, ultimately activating antitumor immunity.