LSTA1 + Standard Care for Advanced Cancers
(BOLSTER Trial)
Recruiting in Palo Alto (17 mi)
+23 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Lisata Therapeutics, Inc.
Disqualifiers: Active infection, Hepatitis, HIV, others
Prior Safety Data
Breakthrough Therapy
Approved in 2 Jurisdictions
Trial Summary
What is the purpose of this trial?This trial is testing a new drug called LSTA1 combined with standard treatment in patients with advanced cholangiocarcinoma. It aims to find out if this combination is safer and more effective than the standard treatment alone.
Will I have to stop taking my current medications?
The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial team or your doctor.
What data supports the effectiveness of the drug LSTA1 (CEND-1) for advanced cancers?
Research shows that CEND-1 helps other cancer drugs work better by making it easier for them to reach and stay in tumors. In studies with animals and patients, CEND-1 was found to stay in tumors longer than in healthy tissues, suggesting it could improve the effectiveness of cancer treatments.
12345Is LSTA1 (CEND-1) safe for human use?
CEND-1 has been studied in both animals and humans, showing a favorable safety profile. In patients with metastatic pancreatic cancer, it was cleared from most healthy tissues within a few hours, suggesting it is generally safe for human use.
12467What makes the drug LSTA1 unique for treating advanced cancers?
LSTA1 (CEND-1) is unique because it is a tumor-targeting peptide that enhances the delivery of other anti-cancer drugs directly into tumors, improving their effectiveness. It works by penetrating the tumor environment and has a prolonged effect, allowing for better drug accumulation in tumors compared to traditional treatments.
12489Eligibility Criteria
This trial is for adults with advanced head and neck squamous cell carcinoma, esophageal squamous cell carcinoma, or cholangiocarcinoma. They must have progressed after first-line therapy, be expected to live at least 3 months, have good organ function and performance status. Exclusions include recent major surgery or radiation, active infections including hepatitis B/C or HIV, certain autoimmune diseases, other cancers treated within the last 3 years, significant heart disease within the past 6 months.Inclusion Criteria
I am fully active or can carry out light work.
My cancer is in my head or neck, has returned or spread, and didn't respond to initial immunotherapy.
Life expectancy ≥ 3 months
+4 more
Exclusion Criteria
I haven't had active treatment for another cancer in the last 3 years, except for certain curable types.
I am allergic to taxanes or their pre-treatments for head and neck cancer.
I do not have active tuberculosis.
+9 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
4 weeks
Run-in
Participants receive LSTA1 or placebo components of their randomized treatment regimen
3 days
Treatment
Participants receive the full treatment regimen, with tumor scans every 8 weeks
Variable, based on individual response
End-of-Treatment Follow-up
Participants have an end-of-treatment follow-up visit
Long-term Follow-up
Participants are monitored for safety and effectiveness after treatment
30 days after treatment discontinuation
Participant Groups
The study tests a new drug called LSTA1 added to standard cancer treatments (like Gemcitabine and Cisplatin) versus just the standard treatments alone. It aims to find out if adding LSTA1 is safe and improves outcomes compared to standard care in patients with specific types of advanced solid tumors.
4Treatment groups
Experimental Treatment
Placebo Group
Group I: LSTA1 arm for Untreated CholangiocarcinomaExperimental Treatment4 Interventions
Group II: LSTA1 arm for Second-Line CholangiocarcinomaExperimental Treatment2 Interventions
Group III: Placebo arm for Second-Line CholangiocarcinomaPlacebo Group2 Interventions
Group IV: Placebo arm for Untreated CholangiocarcinomaPlacebo Group4 Interventions
LSTA1 is already approved in United States, European Union for the following indications:
🇺🇸 Approved in United States as LSTA1 for:
- Orphan drug designation for malignant glioma
- Orphan drug designation for osteosarcoma
- Fast track designation for pancreatic cancer
🇪🇺 Approved in European Union as LSTA1 for:
- Orphan drug designation for pancreatic cancer
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Memorial Healthcare SystemHollywood, FL
Inova Schar Cancer InstituteFairfax, VA
Norton Cancer InstituteLouisville, KY
Mayo Clinica RochesterRochester, MN
More Trial Locations
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Who Is Running the Clinical Trial?
Lisata Therapeutics, Inc.Lead Sponsor
References
Assessment of the Pharmacokinetics, Disposition, and Duration of Action of the Tumour-Targeting Peptide CEND-1. [2023]CEND-1 (iRGD) is a bifunctional cyclic peptide that can modulate the solid tumour microenvironment, enhancing the delivery and therapeutic index of co-administered anti-cancer agents. This study explored CEND-1's pharmacokinetic (PK) properties pre-clinically and clinically, and assessed CEND-1 distribution, tumour selectivity and duration of action in pre-clinical tumour models. Its PK properties were assessed after intravenous infusion of CEND-1 at various doses in animals (mice, rats, dogs and monkeys) and patients with metastatic pancreatic cancer. To assess tissue disposition, [3H]-CEND-1 radioligand was administered intravenously to mice bearing orthotopic 4T1 mammary carcinoma, followed by tissue measurement using quantitative whole-body autoradiography or quantitative radioactivity analysis. The duration of the tumour-penetrating effect of CEND-1 was evaluated by assessing tumour accumulation of Evans blue and gadolinium-based contrast agents in hepatocellular carcinoma (HCC) mouse models. The plasma half-life was approximately 25 min in mice and 2 h in patients following intravenous administration of CEND-1. [3H]-CEND-1 localised to the tumour and several healthy tissues shortly after administration but was cleared from most healthy tissues by 3 h. Despite the rapid systemic clearance, tumours retained significant [3H]-CEND-1 several hours post-administration. In mice with HCC, the tumour penetration activity remained elevated for at least 24 h after the injection of a single dose of CEND-1. These results indicate a favourable in vivo PK profile of CEND-1 and a specific and sustained tumour homing and tumour penetrability. Taken together, these data suggest that even single injections of CEND-1 may elicit long-lasting tumour PK improvements for co-administered anti-cancer agents.
Increasing Tumor Accessibility with Conjugatable Disulfide-Bridged Tumor-Penetrating Peptides for Cancer Diagnosis and Treatment. [2020]Tumor-homing peptides with tissue-penetrating properties increase the efficacy of targeted cancer therapy by delivering an anticancer agent to the tumor interior. LyP-1 (CGNKRTRGC) and iRGD (CRGDKGPDC) are founding members of this class of peptides. The presence of the cysteines forming the cyclizing disulfide bond complicates conjugation of these peptides with other molecules, such as drugs. Here, we report the synthesis of conjugatable disulfide-bridged peptides and their conjugation to biologically important molecules. We have synthesized the LyP-1, iRGD, and CRGDC (GACRGDCLGA) peptides with a cysteine or maleimidohexanoic acid added externally at N-terminus of the sequences. Subsequent conjugation to payloads yielded stable compounds in which the tumor-homing properties of the peptide and the biological activity of the payload were retained.
Selection and identification of ligand peptides targeting a model of castrate-resistant osteogenic prostate cancer and their receptors. [2021]We performed combinatorial peptide library screening in vivo on a novel human prostate cancer xenograft that is androgen-independent and induces a robust osteoblastic reaction in bonelike matrix and soft tissue. We found two peptides, PKRGFQD and SNTRVAP, which were enriched in the tumors, targeted the cell surface of androgen-independent prostate cancer cells in vitro, and homed to androgen receptor-null prostate cancer in vivo. Purification of tumor homogenates by affinity chromatography on these peptides and subsequent mass spectrometry revealed a receptor for the peptide PKRGFQD, α-2-macroglobulin, and for SNTRVAP, 78-kDa glucose-regulated protein (GRP78). These results indicate that GRP78 and α-2-macroglobulin are highly active in osteoblastic, androgen-independent prostate cancer in vivo. These previously unidentified ligand-receptor systems should be considered for targeted drug development against human metastatic androgen-independent prostate cancer.
New multifunctional molecular conjugate vector for targeting, imaging, and therapy of tumors. [2021]We report the in vitro and in vivo characteristics of a new molecular conjugate vector for targeting and imaging of tumors. Its core is a cyclodecapeptide platform named RAFT, onto which two spatially independent functional domains can be covalently and stereospecifically linked: a cell-targeting domain for tumor targeting and a labeling domain able to carry two drugs and/or labeling agents. To prove the interest of this carrier, we used a well-known cRGD cyclopeptide, a ligand for the alphavbeta3 integrin. We demonstrate that this vector presenting four cRGD motifs very efficiently prevents alphavbeta3-mediated cell adhesion to vitronectin. Furthermore, it is actively endocytosed because of the multivalent cRGD presentation, a major advantage for drug delivery. In vivo experiments in nude mice reveal that repeated intratumoral injections of low doses of RAFT(cRGD)4 reduce tumor growth. Furthermore, RAFT(cRGD)4 significantly improves the targeting specificity of subcutaneous tumor masses as well as that of disseminated metastasis after intravenous injection. Thus, RAFT(cRGD)4 is specific, internalized, and perfectly controlled and can carry multiple biological functions on a single, spatially defined backbone, making it a powerful and versatile synthetic vector for drug delivery, molecular imaging, or both.
Transtumoral targeting enabled by a novel neuropilin-binding peptide. [2012]We have recently described a class of peptides that improve drug delivery by increasing penetration of drugs into solid tumors. These peptides contain a C-terminal C-end Rule (CendR) sequence motif (R/K)XX(R/K), which is responsible for cell internalization and tissue-penetration activity. Tumor-specific CendR peptides contain both a tumor-homing motif and a cryptic CendR motif that is proteolytically unmasked in tumor tissue. A previously described cyclic tumor-homing peptide, LyP-1 (sequence: CGNKRTRGC), contains a CendR element and is capable of tissue penetration. We use here the truncated form of LyP-1, in which the CendR motif is exposed (CGNKRTR; tLyP-1), and show that both LyP-1 and tLyP-1 internalize into cells through the neuropilin-1-dependent CendR internalization pathway. Moreover, we show that neuropilin-2 also binds tLyP-1 and that this binding equally activates the CendR pathway. Fluorescein-labeled tLyP-1 peptide and tLyP-1-conjugated nanoparticles show robust and selective homing to tumors, penetrating from the blood vessels into the tumor parenchyma. The truncated peptide is more potent in this regard than the parent peptide LyP-1. tLyP-1 furthermore improves extravasation of a co-injected nanoparticle into the tumor tissue. These properties make tLyP-1 a promising tool for targeted delivery of therapeutic and diagnostic agents to breast cancers and perhaps other types of tumors.
Targeting Ultrasmall Gold Nanoparticles with cRGD Peptide Increases the Uptake and Efficacy of Cytotoxic Payload. [2022]Cyclic arginyl-glycyl-aspartic acid peptide (cRGD) peptides show a high affinity towards αVβ3 integrin, a receptor overexpressed in many cancers. We aimed to combine the versatility of ultrasmall gold nanoparticles (usGNP) with the target selectivity of cRGD peptide for the directed delivery of a cytotoxic payload in a novel design. usGNPs were synthesized with a modified Brust-Schiffrin method and functionalized via amide coupling and ligand exchange and their uptake, intracellular trafficking, and toxicity were characterized. Our cRGD functionalized usGNPs demonstrated increased cellular uptake by αVβ3 integrin expressing cells, are internalized via clathrin-dependent endocytosis, accumulated in the lysosomes, and when loaded with mertansine led to increased cytotoxicity. Targeting via cRGD functionalization provides a mechanism to improve the efficacy, tolerability, and retention of therapeutic GNPs.
In vivo noninvasive optical imaging of receptor-mediated RGD internalization using self-quenched Cy5-labeled RAFT-c(-RGDfK-)(4). [2016]We reported that regioselectively addressable functionalized template (RAFT)-c(-RGDfK-)(4 )presenting four cyclic (Arg-Gly-Asp) (cRGD) peptides targets integrin alpha(V)beta(3) with an improved specificity compared with monomeric cRGD. In this study, we improved this vector by creating a "stealth" molecule in which a fluorescence quencher (Q) is linked to Cy5 via a disulfide bond (-SS-). RAFT-c(-RGDfK-)(4)-Cy5-SS-Q fluorescence is quenched unless activated by reduction during internalization. RAFT-c(-RGDfK-)(4)-Cy5-SS-Q fluorescence was negligible when compared with the control but totally recovered after cleavage of the disulfide bridge. Confocal microscopy showed that only the intracellular Cy5 signal could be detected using RAFT-c(-RGDfK-)(4)-Cy5-SS-Q, confirming that uncleaved extracellular molecules are not visible. Whole-body imaging of mice bearing subcutaneous tumors injected intravenously with RAFT-c(-RGDfK-)(4)-Cy5-SS-Q showed a very significant enhancement of the fluorescent contrast in tumors compared with the unquenched molecule. Histology of the tumor confirmed the intracellular accumulation of Cy5. These results demonstrate that the presence of a labile disulfide bridge between the targeting vector and a drug mimetic is an efficient way to deliver a dye, or a drug, intracellularly. In addition, this quenched RAFT-c(-RGDfK-)(4)-Cy5-SS-Q probe is a very powerful vector for imaging tumor masses and investigating in vivo RGD-mediated internalization.
A free cysteine prolongs the half-life of a homing peptide and improves its tumor-penetrating activity. [2021]The accessibility of extravascular tumor tissue to drugs is critical for therapeutic efficacy. We previously described a tumor-targeting peptide (iRGD) that elicits active transport of drugs and macromolecules (covalently coupled or co-administered) across the vascular wall into tumor tissue. Short peptides (iRGD is a 9-amino acid cyclic peptide) generally have a plasma half-life measured in minutes. Since short half-life limits the window of activity obtained with a bolus injection of iRGD, we explored to extend the half-life of the peptide. We show here that addition of a cysteine residue prolongs the plasma half-life of iRGD and increases the accumulation of the peptide in tumors. This modification prolongs the activity of iRGD in inducing macromolecular extravasation and leads to greater drug accumulation in tumors than is obtained with the unmodified peptide. This effect is mediated by covalent binding of iRGD to plasma albumin through a disulfide bond. Our study provides a simple strategy to improve peptide pharmacokinetics and activity. Applied to RGD, it provides a means to increase the entry of therapeutic agents into tumors.
Theranostic iRGD peptide containing cisplatin prodrug: Dual-cargo tumor penetration for improved imaging and therapy. [2020]In theranostics, peptide-based platforms have widely been exploited owing to their unique biological functions and chemical versatilities. As a tumor-homing ligand, internalizing RGD peptide (iRGD), composed of a tumor-targeting sequence (RGD) and a cell-penetrating C-end Rule (CendR) motif, is known to facilitate the tumor-specific delivery of payloads that are covalently conjugated on its N-terminal fragment or co-administered without any covalent linkages. However, theranostic uses of the iRGD-based platform remain in its infancy with its full potential unexplored; for instance, detailed mechanism of iRGD fragmentation during internalization, strategies for the tumor-specific release of payloads from iRGD and the role of the C-terminal iRGD fragment in delivery have yet to be revealed. In this study, we designed a dual-channel fluorescent cyclic iRGD (TAMRA-iRGDC-Cy5.5) to track each of the N- and C-terminal fragments separately during the tumor internalization process. It turned out that both fragments undergo translocation into cancer cells together and are localized within endosomal-lysosomal compartments. The resulting co-internalization of both iRGD fragments allowed us to develop a new theranostic peptide platform (Cy5.5-iRGDC-Pt(IV)) by conjugating a fluorescent dye and a cisplatin prodrug on each terminus of cyclic iRGD for simultaneous cancer-targeted imaging and therapy. Compared to a control peptide having a non-iRGD sequence, the Cy5.5-iRGDC-Pt(IV) did not only provide a better tumor imaging contrast but also induced tumor-specific apoptosis leading to efficacious tumor suppression. Besides the outstanding cancer imaging and therapeutic performance, the Cy5.5-iRGDC-Pt(IV) revealed negligible systemic toxicity, holding potential to be applied for theranostic uses.