PT0253 for Cancer

Recruiting at 5 trial locations

Overseen By PAQ Therapeutics

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: PAQ Therapeutics, Inc.

Must not be taking: CYP3A4/5 inhibitors, P-gp inhibitors

Disqualifiers: Active brain metastasis, Significant cardiovascular disease, Active infection, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

115 Participants Needed

Trial Summary

What is the purpose of this trial?

The primary purpose of this study is to evaluate the safety and tolerability, determine the maximally tolerated dose (MTD) and/or recommended Phase 2 dose(s) (RP2D) of PT0253 in adult participants with Kirsten rat sarcoma viral oncogene homolog (KRAS) G12D mutated advanced solid tumors as monotherapy.

Will I have to stop taking my current medications?

The trial requires that you stop taking anticancer medications or investigational drugs 14-28 days before starting the study drug. However, concurrent hormonal therapy for prostate or breast cancer is allowed. If you are using certain medications like strong or moderate CYP3A4/5 inhibitors or inducers, you may need to stop them before the trial.

What data supports the effectiveness of the drug PT0253 for cancer?

Research on Radium-223, a component similar to PT0253, shows it can extend survival in prostate cancer patients with bone metastases and has shown promise in breast cancer patients with bone disease. It reduces bone-related complications and improves survival, especially when patients complete more treatment cycles. ^{1 2 3 4 5}

What safety information is available for PT0253 (also known as 254-S) in humans?

PT0253, also known as 254-S, has been tested in humans and showed some side effects like low blood cell counts (thrombocytopenia and leukopenia) and stomach issues (nausea and vomiting), but these were generally manageable and did not require stopping the treatment. It was found to have less severe kidney and stomach side effects compared to similar drugs like cisplatin. ^{6 7 8 9 10}

How is the drug PT0253 different from other cancer treatments?

PT0253, also known as VX15/2503, is a humanized antibody targeting Semaphorin 4D, which is unique because it focuses on a specific protein involved in tumor growth and spread, unlike traditional chemotherapy that targets rapidly dividing cells in general. ^{11 12 13 14 15}

Eligibility Criteria

This trial is for adults with advanced solid tumors that have a specific mutation called KRAS G12D. The exact eligibility criteria are not provided, but typically participants must be in good health aside from their cancer and meet certain lab test requirements.

Inclusion Criteria

Measurable disease (RECIST 1.1 Criteria)

Willingness to avoid pregnancy or fathering children from screening through 90 days after the last dose of study treatment

My cancer is confirmed to be advanced or has spread.

Exclusion Criteria

Known HIV infection with specific criteria

I have a known history of liver conditions.

I am not pregnant, breastfeeding, nor planning to breastfeed.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants with any type of solid tumor will receive PT0253 injection, intravenously (IV) until disease progression or intolerance

Until disease progression or intolerance

Dose Expansion

Participants with a previously treated tumor type will receive PT0253 injection until disease progression or intolerance. Recommended dose or doses for expansion will be determined based on the safety, tolerability, PK and PD data established in Dose Escalation

Until disease progression or intolerance

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 24 months

Treatment Details

Interventions

• PT0253

Trial Overview The study is testing PT0253, a new potential treatment for cancer. It aims to find the highest dose patients can take without serious side effects (MTD) and suggest doses for future Phase 2 trials (RP2D).

Participant Groups

Group I: Part 1b, Dose Expansion: Tumor type 3 Experimental Treatment 1 Intervention

Participants with a previously treated tumor type will receive PT0253 injection until disease progression or intolerance. Recommended dose or doses for expansion for Part 1b will be determined based on the safety, tolerability, PK and PD data for PT0253 established in Part 1a.

Group II: Part 1b, Dose Expansion: Tumor type 2 Experimental Treatment 1 Intervention

Participants with a previously treated tumor type will receive PT0253 injection until disease progression or intolerance. Recommended dose or doses for expansion for Part 1b will be determined based on the safety, tolerability, PK and PD data for PT0253 established in Part 1a.

Group III: Part 1b, Dose Expansion: Tumor type 1 Experimental Treatment 1 Intervention

Participants with a previously treated tumor type will receive PT0253 injection until disease progression or intolerance. Recommended dose or doses for expansion for Part 1b will be determined based on the safety, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) data for PT0253 established in Part 1a.

Group IV: Part 1a, Dose Escalation Experimental Treatment 1 Intervention

Participants with any type of solid tumor will receive PT0253 injection, intravenously (IV) until disease progression or intolerance.

Who Is Running the Clinical Trial?

PAQ Therapeutics, Inc.

Lead Sponsor

Trials

1

Recruited

120+

Findings from Research

In a study of 92 mCRPC patients treated with 223Ra, baseline clinical variables such as hemoglobin (Hb) levels and ECOG performance status were found to be significant predictors of overall survival, highlighting their importance in treatment planning.

A predictive scoring system combining ECOG PS, Hb levels below 12 g/dl, and PSA levels of 20 ng/ml or higher was developed, achieving an area under the curve (AUC) of 78.4%, which can help identify patients who are likely to benefit most from 223Ra therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A 3-variable prognostic score (3-PS) for overall survival prediction in metastatic castration-resistant prostate cancer treated with 223Radium-dichloride. Frantellizzi, V., Farcomeni, A., Follacchio, GA., et al.[2019]

Radium 223 dichloride (Ra223) is the only targeted alpha therapy that has been shown to extend survival in patients with bone metastases from prostate cancer, and it may also be effective for breast cancer patients with bone disease.

A case study at our institution demonstrated that Ra223 was safely used off-label in a breast cancer patient with osteolytic metastases, showing good treatment compliance and no significant side effects or hematological complications, suggesting its potential role in treating bone metastases in breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic effect of RA223 in the management of breast cancer bone metastases. Costa, RP., Tripoli, V., Princiotta, A., et al.[2019]

In a review of 28 mCRPC patients treated with off-label Ra-223, the median overall survival (OS) was 15.6 months, with better outcomes for those receiving 5-6 treatment cycles (18.5 months) compared to those receiving 4 or fewer cycles (9.1 months).

Ra-223 treatment significantly reduced the occurrence of bone events, with 76.2% of patients completing 6 cycles experiencing no bone events, highlighting the importance of completing more cycles for better patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-center developing country analysis of radium-223 therapy in prostate cancer-preliminary results. Minekawa, TB., Santos, AO., Moraes, AG., et al.[2023]

In a study of 110 patients with metastatic castration-resistant prostate cancer treated with (223)Ra, significant reductions in alkaline phosphatase (ALP) levels and pain scores were observed throughout the treatment cycles, indicating effective symptom management.

The total number of (223)Ra cycles and the use of abiraterone were strongly associated with improved overall survival and progression-free survival, suggesting that combining these treatments may enhance patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Factors affecting (223)Ra therapy: clinical experience after 532 cycles from a single institution. Etchebehere, EC., Milton, DR., Araujo, JC., et al.[2022]

In a study of 150 men with metastatic castration-resistant prostate cancer treated with radium-223, the median overall survival was 14.5 months, highlighting its efficacy in improving survival for patients with bone metastases.

Key pre-treatment factors such as low albumin, high alkaline phosphatase, poor performance status, and high prostate-specific antigen levels were identified as predictors of poor survival, allowing for the development of a prognostic model to better select patients who may benefit from radium-223 treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinicopathologic factors that influence prognosis and survival outcomes in men with metastatic castration-resistant prostate cancer treated with Radium-223. Al-Ezzi, EM., Alqaisi, HA., Iafolla, MAJ., et al.[2022]

In a phase II clinical study involving 19 patients with advanced breast cancer, the new platinum complex 254-S showed a partial response rate of 12.5%, indicating some efficacy in tumor reduction.

The treatment was associated with significant side effects, including hematotoxicity (thrombocytopenia and leukopenia) and gastrointestinal issues (nausea, vomiting, and anorexia), but none of the patients required discontinuation of the treatment due to these toxic effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[A phase II clinical study of cis-diammine glycolato platinum, 254-S, for advanced breast cancer]. Koyama, H., Ogawa, M., Kuraishi, Y., et al.[2012]

The new platinum complex 254-S shows a better safety profile than cisplatin, with reduced renal and gastrointestinal toxicities, making it a promising alternative for cancer treatment.

In a Phase I clinical study involving 28 patients, 254-S was well tolerated, with a maximum tolerated dose of 120 mg/m2, and the recommended dose for further studies set at 100 mg/m2, indicating its potential for effective cancer therapy with fewer side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Phase I study of a new platinum complex 254-S, cis-diammine (glycolato)-platinum (II)]. Ota, K., Wakui, A., Majima, H., et al.[2012]

The maximum tolerated dose (MTD) of the new platinum derivative SKI 2053R was determined to be 480 mg/m², with significant dose-limiting toxicities including hepatotoxicity, nephrotoxicity, and myelosuppression observed at this level.

At doses up to 360 mg/m², SKI 2053R showed manageable toxicity and resulted in stable disease in 4 out of 21 patients, suggesting potential efficacy for further investigation in a Phase II study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase I study of cis-malonato[(4R,5R)-4,5-bis(aminomethyl)-1,3-dioxolane] platinum(II) in patients with advanced malignancies. Kim, NK., Kim, TY., Shin, SG., et al.[2019]

CI-973 shows promising efficacy in preclinical models, demonstrating activity comparable or superior to cisplatin and carboplatin, and is effective against cisplatin-resistant cancer cell lines.

In a phase I trial with 28 patients, CI-973 exhibited a favorable safety profile with no renal or auditory toxicity, although mild to moderate nausea and vomiting were common; the maximum tolerated dose was determined to be 290 mg/m2 for patients with good performance status.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I clinical evaluation of [SP-4-3(R)]-[1,1-cyclobutanedicarboxylato(2-)](2-methyl-1,4- butanediamine-N,N1) platinum in patients with metastatic solid tumors. Theriault, RL., Cohen, IA., Esparza, L., et al.[2019]

In a phase II study involving 66 patients with advanced breast cancer, the combination of paclitaxel and carboplatin resulted in a total response rate of 53%, with 12% achieving a complete response and 41% a partial response.

The treatment was generally well-tolerated, with manageable toxicities, allowing for outpatient administration, and a median time to progression of 8.9 months, indicating significant activity against advanced breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paclitaxel and carboplatin as first-line chemotherapy for advanced breast cancer. Fountzilas, G., Athanassiades, A., Papadimitriou, V., et al.[2015]

ZD0473, a new platinum-based drug, demonstrated linear pharmacokinetics and was well-tolerated in a Phase I study involving 9 Japanese patients with solid tumors, with no significant nephro-, oto-, or neurotoxicity observed.

The treatment showed evidence of disease stabilization in 33% of patients, indicating potential efficacy, although the trial was halted following changes in the development program after evaluating data from Western trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ZD0473 pharmacokinetics in Japanese patients: a Phase I dose-escalation study. Murakami, H., Tamura, T., Yamada, Y., et al.[2019]

In a phase II study involving 33 women with metastatic breast cancer, ZD0473 showed limited efficacy as a single agent, achieving a response rate of only 3.8% with one partial response observed.

The treatment was associated with significant hematological toxicity, particularly at the higher dose of 150 mg/m², where 60% of patients experienced severe thrombocytopenia and 75% experienced severe neutropenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II study of ZD0473 given as a short infusion every 3 weeks to patients with advanced or metastatic breast cancer: a National Cancer Institute of Canada Clinical Trials Group trial, IND 129. Gelmon, KA., Vandenberg, TA., Panasci, L., et al.[2020]

VX15/2503 was well tolerated in a study of 42 patients with advanced solid tumors, with most side effects being mild (grade 1 or 2), such as nausea and fatigue, indicating a favorable safety profile.

The treatment showed promising antitumor activity, with one patient achieving a partial response and 45.2% of patients maintaining stable disease for at least 8 weeks, suggesting that VX15/2503 may enhance immune response against tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, Pharmacokinetics, and Pharmacodynamics of a Humanized Anti-Semaphorin 4D Antibody, in a First-In-Human Study of Patients with Advanced Solid Tumors. Patnaik, A., Weiss, GJ., Leonard, JE., et al.[2022]

miR-203 is found to be upregulated in breast cancer tissues and the MCF-7 cell line, and its knockdown leads to reduced colony formation, transformation, and migration of cancer cells, suggesting its role in promoting cancer progression.

FGF2 was identified as a novel target of miR-203; when miR-203 is knocked down, FGF2 expression increases, which may help suppress breast cancer by reversing the transforming growth factor-β signaling pathway.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

miR-203 facilitates tumor growth and metastasis by targeting fibroblast growth factor 2 in breast cancer. He, S., Zhang, G., Dong, H., et al.[2022]

In a phase I study involving 23 patients with refractory solid tumors, the combination of ZD0473 and paclitaxel demonstrated a manageable safety profile, with dose-limiting thrombocytopenia identified at the maximum tolerated dose of 150 mg/m2 ZD0473 and 175 mg/m2 paclitaxel.

The treatment showed promising antitumor activity, with 47.8% of patients experiencing disease stabilization, including significant tumor reductions in some patients with non-small-cell lung cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I study of ZD0473 combined with paclitaxel for the treatment of solid malignancies. Twelves, C., Reck, M., Anthoney, A., et al.[2015]

References

1. Japan pubmed.ncbi.nlm.nih.gov

A 3-variable prognostic score (3-PS) for overall survival prediction in metastatic castration-resistant prostate cancer treated with 223Radium-dichloride. [2019]

2. Italy pubmed.ncbi.nlm.nih.gov

Therapeutic effect of RA223 in the management of breast cancer bone metastases. [2019]

3. United States pubmed.ncbi.nlm.nih.gov

Single-center developing country analysis of radium-223 therapy in prostate cancer-preliminary results. [2023]

4. Germany pubmed.ncbi.nlm.nih.gov

Factors affecting (223)Ra therapy: clinical experience after 532 cycles from a single institution. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Clinicopathologic factors that influence prognosis and survival outcomes in men with metastatic castration-resistant prostate cancer treated with Radium-223. [2022]

6. Japan pubmed.ncbi.nlm.nih.gov

[A phase II clinical study of cis-diammine glycolato platinum, 254-S, for advanced breast cancer]. [2012]

7. Japan pubmed.ncbi.nlm.nih.gov

[Phase I study of a new platinum complex 254-S, cis-diammine (glycolato)-platinum (II)]. [2012]

8. United States pubmed.ncbi.nlm.nih.gov

A Phase I study of cis-malonato[(4R,5R)-4,5-bis(aminomethyl)-1,3-dioxolane] platinum(II) in patients with advanced malignancies. [2019]

9. Germany pubmed.ncbi.nlm.nih.gov

Phase I clinical evaluation of [SP-4-3(R)]-[1,1-cyclobutanedicarboxylato(2-)](2-methyl-1,4- butanediamine-N,N1) platinum in patients with metastatic solid tumors. [2019]

10. United States pubmed.ncbi.nlm.nih.gov

Paclitaxel and carboplatin as first-line chemotherapy for advanced breast cancer. [2015]

11. England pubmed.ncbi.nlm.nih.gov

ZD0473 pharmacokinetics in Japanese patients: a Phase I dose-escalation study. [2019]

12. England pubmed.ncbi.nlm.nih.gov

A phase II study of ZD0473 given as a short infusion every 3 weeks to patients with advanced or metastatic breast cancer: a National Cancer Institute of Canada Clinical Trials Group trial, IND 129. [2020]

13. United States pubmed.ncbi.nlm.nih.gov

Safety, Pharmacokinetics, and Pharmacodynamics of a Humanized Anti-Semaphorin 4D Antibody, in a First-In-Human Study of Patients with Advanced Solid Tumors. [2022]

14. New Zealand pubmed.ncbi.nlm.nih.gov

miR-203 facilitates tumor growth and metastasis by targeting fibroblast growth factor 2 in breast cancer. [2022]

15. Germany pubmed.ncbi.nlm.nih.gov

A phase I study of ZD0473 combined with paclitaxel for the treatment of solid malignancies. [2015]