CRX100 for Solid Cancers

Recruiting at 2 trial locations

Overseen By Jennifer Lindal

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: BioEclipse Therapeutics

Must not be taking: Immunosuppressants, Corticosteroids

Disqualifiers: Brain metastasis, Active infections, Autoimmune disease, HIV, others

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

Compensation: Varies

Number of Visits: 109

60 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications. However, you cannot participate if you have received chemotherapy, immunotherapies, or certain other treatments within three weeks of enrollment, or cell-based therapies within 12 weeks. It's best to discuss your specific medications with the trial team.

What safety data exists for CRX100 or similar treatments in humans?

There is no specific safety data available for CRX100, but similar treatments like crizotinib have been studied for safety in children with solid tumors, and other treatments like trastuzumab deruxtecan have shown common side effects such as decreased neutrophil count and anemia in adults with cancer. ^{1 2 3 4 5}

What makes the drug CRX100 unique for treating solid cancers?

CRX100 is unique because it targets the nuclear export protein CRM1, which is involved in transporting proteins and RNAs from the nucleus to the cytoplasm, a process crucial for cancer cell survival and proliferation. This mechanism is different from many standard cancer treatments, which often target cell division or DNA replication directly. ^{6 7 8 9 10}

What is the purpose of this trial?

This clinical study is an open-label, Phase 1, dose-escalation study to determine the safety, tolerability, and efficacy of the drug product produced by Administering CRX100 alone and in combination with Pembrolizumab in advanced solid malignancies. Patients will be screened and evaluated to determine whether or not they meet stated inclusion criteria. Enrolled subjects will undergo leukapheresis to enable the ex vivo generation of CRX100. Patients with non-small cell lung cancer (NSCLC), ovarian cancer, colorectal cancer, hepatocellular carcinoma (HCC), malignant melanoma (excluding uveal melanoma), gastric cancer, triple negative breast cancer, and osteosarcoma. The study will start with monotherapy dose escalation followed by combination cohorts.

Research Team

Oliver Dorigo

Principal Investigator

Stanford University

Eligibility Criteria

Adults over 18 with advanced solid tumors like certain breast, colorectal, liver, bone, ovarian or stomach cancers can join. They should be recovered from past treatments and free of active infections. Participants must have measurable cancer on scans and agree to use contraception. Those with recent immunosuppressants, other cancers or treatments, serious illnesses including HIV/hepatitis B/C or brain metastasis cannot join.

Inclusion Criteria

I will use effective birth control during and for 6 months after the study.

I have recovered from recent surgery, radiation, or chemotherapy.

My cancer can be measured by scans and has at least one visible tumor.

Exclusion Criteria

I or someone I live with has a significant immune system problem.

I haven't had experimental drugs or immunotherapy in the last 3 weeks.

I have or had an autoimmune disease, with some exceptions.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Monotherapy Dose-Escalation

Participants receive CRX100 as monotherapy with dose escalation to determine safety and tolerability

Up to 36 weeks

Infusions every 9 weeks, up to 4 infusions

Combination Therapy

Participants receive CRX100 in combination with Pembrolizumab to evaluate safety and anti-tumor activity

Up to 36 weeks

CRX100 infusions every 9 weeks, Pembrolizumab every 3 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Treatment Details

Interventions

• CRX100

Trial Overview CRX100 is being tested in this phase 1 trial for safety and how the body processes it. It involves taking patients' immune cells out (leukapheresis), treating them to become 'cytokine induced killer cells', then putting them back into the patient to fight cancer.

Participant Groups

Group I: Monotherapy Dose-Escalation Cohorts Experimental Treatment 3 Interventions

Prior to the current amendment, no DLTs were observed at Dose Levels 1-5. Starting with the current protocol amendment, dosing decisions in monotherapy cohorts will utilize a 3+3 design for Dose Level 6. CRX100 infusion will occur every nine weeks (+/- 7 days). Subjects will receive up to a maximum of four infusions of CRX100 unless it is determined by the treating physician and the sponsor that it is in the best interest of the subjects to receive additional doses of CRX100 beyond four doses. A minimum of three DLT-evaluable subjects will be doses at Dose Level 6 and expanded to six subjects if determined necessary based on DLT incidence using the 3+3 design, and discussion with SRC and Sponsor.

Group II: Combination Therapy Cohorts Experimental Treatment 3 Interventions

Subjects with relasped or refractory solid tumors, as defined in the inclusion criteria, will be enrolled to evaluate the safety and anti-tumor activity of CRX100 in combination with Pembrolizumab in patients with advanced solid malignancies. The dose of CRX100 used will be determined from the monotherapy cohorts. CRX100 infusion will occur every nine weeks (+/- 7 days). Subjects will receive up to a maximum of four doses of CRX100 unless it is determined by the treating physician and the sponsor that it is in the best interest of the subjects to receive additional doses of CRX100 beyond four doses. Pembrolizumab will be administered at 200mg IV every three weeks (Q3W) per the approved label.

Who Is Running the Clinical Trial?

BioEclipse Therapeutics

Lead Sponsor

Trials

1

Recruited

60+

Findings from Research

In a phase 1 study involving 44 pediatric patients with refractory solid tumors and ALCL, the recommended phase 2 dose (RP2D) of crizotinib in combination with topotecan and cyclophosphamide was determined to be 215 mg/m2/dose taken twice daily, showing it can be safely tolerated at this dosage.

The study found that while the oral solution of crizotinib was not well tolerated due to palatability issues, the crizotinib formulated capsules were more acceptable, although they led to increased toxicity that requires further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, tolerability and pharmacokinetics of crizotinib in combination with cytotoxic chemotherapy for pediatric patients with refractory solid tumors or anaplastic large cell lymphoma (ALCL): a Children's Oncology Group phase 1 consortium study (ADVL1212). Greengard, E., Mosse, YP., Liu, X., et al.[2021]

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]

The North Central Cancer Treatment Group developed a real-time toxicity reporting system to enhance the monitoring of severe side effects in NCI-sponsored clinical trials, aiming to improve patient safety.

This system has been effective in monitoring phase II and III trials, such as the N9741 study on advanced colorectal cancer, allowing for timely modifications to ongoing clinical trials based on reported adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early detection of toxicity and adjustment of ongoing clinical trials: the history and performance of the North Central Cancer Treatment Group's real-time toxicity monitoring program. Goldberg, RM., Sargent, DJ., Morton, RF., et al.[2016]

In the DESTINY-CRC01 trial involving 86 patients with HER2-expressing metastatic colorectal cancer, trastuzumab deruxtecan (T-DXd) showed a significant objective response rate of 45.3% in patients with HER2-positive tumors (cohort A), while no responses were observed in cohorts with lower HER2 expression.

The treatment demonstrated a median progression-free survival of 6.9 months and an overall survival of 15.5 months, with manageable safety concerns, including a 9.3% incidence of drug-related interstitial lung disease/pneumonitis, indicating T-DXd's potential as a targeted therapy for HER2-positive mCRC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Final results of DESTINY-CRC01 investigating trastuzumab deruxtecan in patients with HER2-expressing metastatic colorectal cancer. Yoshino, T., Di Bartolomeo, M., Raghav, K., et al.[2023]

In a multicenter phase II study involving 71 patients with metastatic breast cancer, Caelyx (Doxil) demonstrated an overall response rate of 31%, with 16 patients achieving a partial or complete response, indicating its efficacy in treating advanced breast cancer.

The safety profile of Caelyx was favorable, with significant neutropenia and mucositis occurring in only 10% of treatment cycles, and a lower incidence of severe skin toxicity at a dose of 45 mg/m2 every 4 weeks, suggesting it is well-tolerated and suitable for combination chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of advanced breast cancer with sterically stabilized liposomal doxorubicin: results of a multicenter phase II trial. Ranson, MR., Carmichael, J., O'Byrne, K., et al.[2017]

The novel CRM1 inhibitor KPT-185 effectively reduced the viability of non-small cell lung cancer (NSCLC) cell lines, including those resistant to EGFR-TKIs, by inducing cell cycle arrest and apoptosis in a dose-dependent manner.

In an in vivo mouse model, the clinical analog KPT-276 significantly inhibited tumor growth without causing significant side effects, indicating its potential as a safe therapeutic option for NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor effects of a novel chromosome region maintenance 1 (CRM1) inhibitor on non-small cell lung cancer cells in vitro and in mouse tumor xenografts. Wang, S., Han, X., Wang, J., et al.[2023]

Elevated levels of HOXC10 in colorectal cancer (CRC) patients are associated with increased metastasis, poorer tumor differentiation, and worse overall prognosis, making it a significant independent predictor of patient outcomes.

Targeting the HOXC10-CXCL5-MDSC pathway with CXCR2 inhibitors or anti-PD-L1 treatments shows promise in reducing CRC metastasis, suggesting new therapeutic strategies for patients with high HOXC10 expression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

HOXC10 Promotes Metastasis in Colorectal Cancer by Recruiting Myeloid-derived Suppressor Cells. Yu, J., Chen, X., Zhao, S., et al.[2022]

CRX (OTX3) is a transcription factor that is crucial for the development of retinal and pineal cells, and it is selectively expressed in retinoblastomas and pineal tumors, making it a potential marker for diagnosing these cancers.

In a study of 89 central nervous system tumors, CRX was found to be a strong marker in normal pineal tissue and pineal tumors, but its absence does not completely rule out the diagnosis of pineal parenchymal tumors, especially in small biopsy samples.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CRX/OTX3: a useful marker in the differential diagnosis of tumors of the pineal region and indicator of photoreceptor differentiation in medulloblastomas and atypical teratoid rhabdoid tumors. Gielen, GH., Gessi, M., Denkhaus, D., et al.[2016]

Crm1, a nuclear export receptor, is significantly overexpressed in oesophageal squamous cell carcinoma compared to normal tissues, indicating its potential role in cancer progression.

Inhibiting Crm1 expression in oesophageal cancer cells led to reduced cell proliferation and increased apoptosis, suggesting that targeting Crm1 could be a promising therapeutic strategy with minimal effects on normal oesophageal cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Elevated expression of the nuclear export protein, Crm1 (exportin 1), associates with human oesophageal squamous cell carcinoma. van der Watt, PJ., Zemanay, W., Govender, D., et al.[2023]

CRX is a transcription factor that is specifically expressed in retinal and pineal cells, and its strong expression in over 95% of retinoblastomas and pineal parenchymal tumors suggests it could serve as a sensitive and specific clinical marker for these cancers.

The study indicates that CRX may also be a potential therapeutic target for retinoblastoma and pineoblastoma, as it is not commonly found in other tumors, making it a promising candidate for lineage-dependent cancer treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CRX is a diagnostic marker of retinal and pineal lineage tumors. Santagata, S., Maire, CL., Idbaih, A., et al.[2021]

References

1. Germany pubmed.ncbi.nlm.nih.gov

Safety, tolerability and pharmacokinetics of crizotinib in combination with cytotoxic chemotherapy for pediatric patients with refractory solid tumors or anaplastic large cell lymphoma (ALCL): a Children's Oncology Group phase 1 consortium study (ADVL1212). [2021]

2. 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]

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

Early detection of toxicity and adjustment of ongoing clinical trials: the history and performance of the North Central Cancer Treatment Group's real-time toxicity monitoring program. [2016]

4. England pubmed.ncbi.nlm.nih.gov

Final results of DESTINY-CRC01 investigating trastuzumab deruxtecan in patients with HER2-expressing metastatic colorectal cancer. [2023]

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

Treatment of advanced breast cancer with sterically stabilized liposomal doxorubicin: results of a multicenter phase II trial. [2017]

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

Antitumor effects of a novel chromosome region maintenance 1 (CRM1) inhibitor on non-small cell lung cancer cells in vitro and in mouse tumor xenografts. [2023]

7. Australia pubmed.ncbi.nlm.nih.gov

HOXC10 Promotes Metastasis in Colorectal Cancer by Recruiting Myeloid-derived Suppressor Cells. [2022]

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

CRX/OTX3: a useful marker in the differential diagnosis of tumors of the pineal region and indicator of photoreceptor differentiation in medulloblastomas and atypical teratoid rhabdoid tumors. [2016]

9. Greece pubmed.ncbi.nlm.nih.gov

Elevated expression of the nuclear export protein, Crm1 (exportin 1), associates with human oesophageal squamous cell carcinoma. [2023]

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

CRX is a diagnostic marker of retinal and pineal lineage tumors. [2021]