Zotatifin for Solid Tumors

(Zotatifin Trial)

Recruiting at17 trial locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: Effector Therapeutics

Must be taking: CDK4/6 inhibitors

Disqualifiers: KRAS G12C mutations, others

No Placebo Group

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This trial is testing a new drug called Zotatifin for patients with advanced cancers that haven't improved with standard treatments. The drug works by stopping cancer cells from making essential proteins, which may slow or stop the cancer.

Do I have to stop taking my current medications for the Zotatifin trial?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug Zotatifin for solid tumors?

The research does not provide direct evidence for Zotatifin's effectiveness, but similar drugs targeting pathways like EGFR have shown promise in treating various solid tumors, suggesting potential for Zotatifin. ^{1 2 3 4 5}

What makes the drug Zotatifin unique for treating solid tumors?

Zotatifin is unique because it targets the eukaryotic translation initiation factor 4A (eIF4A), which is a novel approach compared to other treatments that often target pathways like EGFR or PI3K/mTOR. This mechanism may offer a new way to inhibit tumor growth in solid tumors. ^{1 6 7 8 9}

Research Team

Douglas Warner, MD

Principal Investigator

EFFECTOR Therapeutics, Inc.

Eligibility Criteria

This trial is for adults with certain advanced solid tumors who've had previous treatments like CDK4/6 inhibitors and are now facing cancer that's resistant or intolerant to standard therapies. They should have tried at least one, but no more than five lines of therapy for metastatic disease, and specific criteria apply based on the type of tumor (ER+, HER2-, KRAS mutation, etc.).

Inclusion Criteria

I have had at least one HER2-targeted treatment.

I have had no more than five treatments for my advanced cancer.

My breast cancer diagnosis was confirmed through lab tests.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive eFT226 in dose-escalation cohorts to determine the Recommended Phase 2 Dose (RP2D) and Maximum Tolerated Dose (MTD)

21-day cycles for Part 1a and 14-day cycles for Part 1b

Cohort Expansion

Further exploration of safety, pharmacology, and clinical activity of eFT226 monotherapy and in combination with other therapies

Approximately 12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• eFT226 (Translation Inhibitor)

Trial Overview The study tests Zotatifin (eFT226) alongside other drugs like Abemaciclib, Fulvestrant, Trastuzumab, and Sotorasib in a Phase 1-2 trial. It aims to find out how safe eFT226 is and how it affects the body (pharmacokinetics/dynamics) as well as its effectiveness against various solid tumors.

Participant Groups

Group I: Part 2: Cohort Expansion, Monotherapy, NSCLC, KRAS (EMNK) Experimental Treatment 1 Intervention

Cohort EMNK

Group II: Part 2: Cohort Expansion, Monotherapy, Breast, HER2 (EMBH) Experimental Treatment 1 Intervention

Cohort EMBH

Group III: Part 2: Cohort Expansion, Monotherapy, Breast, FGFR (EMBF) Experimental Treatment 1 Intervention

Cohort EMBF

Group IV: Part 2: Cohort Expansion, Combination, NSCLC, Sotorasib (ECNS) Experimental Treatment 1 Intervention

Cohort ECNS; Combination therapy partner administered per SOC at the approved dose.

Group V: Part 2: Cohort Expansion, Combination, Breast, Trastuzumab (ECBT) Experimental Treatment 1 Intervention

Cohort ECBT; Combination therapy partner administered per SOC at the approved dose.

Group VI: Part 2: Cohort Expansion, Combination, Breast, Fulvestrant+Abemaciclib (ECBF+A) Experimental Treatment 2 Interventions

Cohort ECBF+A; Combination therapy partner administered per SOC at the approved dose.

Group VII: Part 2: Cohort Expansion, Combination, Breast, Fulvestrant (ECBF) Experimental Treatment 1 Intervention

Cohort ECBF; Combination therapy partner administered per SOC at the approved dose.

Group VIII: Part 2 Cohort Expansion, Combination, Breast, Fulvestrant, Cyclin D1 Experimental Treatment 1 Intervention

ECBF-D1; Combination therapy partner administered per SOC at the approved dose.

Group IX: Part 1b Dose Escalation, Combination, Breast Experimental Treatment 1 Intervention

eFT226 administered IV every other week in 14-day cycles. Fulvestrant will also be given. Dose escalations per protocol.

Group X: Part 1a: Dose Escalation, Combination, Breast Experimental Treatment 1 Intervention

eFT226 administered IV weekly in 21-day cycles. Fulvestrant will also be given. Dose escalations per protocol.

Group XI: Part 1: Sequential escalation (Completed) Experimental Treatment 1 Intervention

eFT226 administered IV weekly in 21-day cycles; dose escalated in sequential cohorts after subjects enrolled in a given cohort have completed DLT evaluation period.

Who Is Running the Clinical Trial?

Effector Therapeutics

Lead Sponsor

Trials

11

Recruited

600+

Findings from Research

The combination of the EGFR inhibitor erlotinib and the NF-kB inhibitor ixazomib was found to be safe and well tolerated in a Phase I study involving 19 patients with advanced solid tumors, with common side effects including diarrhea (42.1%) and rash (36.8%).

While no patients achieved significant tumor shrinkage, three patients with advanced sarcoma experienced stable disease for at least 6 months, suggesting potential antitumor activity of this drug combination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase i study of ixazomib and erlotinib in patients with advanced solid tumors. Kato, S., Adashek, JJ., Subbiah, V., et al.[2022]

EGFR-targeting agents like C225 and ZD1839 show promise in treating cancers such as non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC), with C225 demonstrating synergy with chemotherapy and radiation in preclinical models.

Despite initial positive responses in phase I trials, large phase III studies of ZD1839 combined with chemotherapy did not show an increase in survival for advanced NSCLC patients, highlighting the need for further research into effective treatment combinations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The epidermal growth factor receptor pathway and its inhibition as anticancer therapy. Janmaat, ML., Giaccone, G.[2022]

Axitinib is an oral medication that inhibits key receptors involved in tumor growth and has shown activity against various solid tumors, including thyroid, pancreatic, lung, and breast cancers, based on Phase II trials.

While common side effects include fatigue and hypertension, axitinib was generally well tolerated, and larger randomized studies were underway to further evaluate its efficacy and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Axitinib, a novel anti-angiogenic drug with promising activity in various solid tumors. Choueiri, TK.[2018]

Epidermal growth factor receptor (EGFR) inhibitors like erlotinib and gefitinib have shown established clinical activity in treating non-small cell lung cancer, with newer agents like ZD6474 showing promising antitumor activity in clinical trials.

Several new EGFR inhibitors are in advanced testing, indicating that EGFR is a validated target for cancer treatment, and future research will focus on their effectiveness in patients who have not responded to existing EGFR therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Epidermal growth factor receptor inhibitors in development for the treatment of non-small cell lung cancer. Heymach, JV., Nilsson, M., Blumenschein, G., et al.[2018]

Pyrotinib is an irreversible dual pan-ErbB receptor tyrosine kinase inhibitor that has received conditional approval in China for treating HER2-positive advanced breast cancer, specifically in patients who have already undergone anthracycline or taxane chemotherapy.

The approval was based on positive results from a phase II trial, highlighting its efficacy in combination with capecitabine for this specific patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pyrotinib: First Global Approval. Blair, HA.[2019]

The combination of BGT226, a dual PI3K/mTOR inhibitor, and gefitinib showed enhanced anti-tumor effects in non-small cell lung cancer (NSCLC) cell lines, particularly in those sensitive to gefitinib, indicating a potential new treatment strategy.

In xenograft models, this combination therapy not only inhibited tumor growth more effectively than either drug alone but also increased apoptosis and further inhibited the PI3K/mTOR signaling pathway, suggesting a synergistic mechanism of action.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synergistic anti-tumor effects of a novel phosphatidyl inositol-3 kinase/mammalian target of rapamycin dual inhibitor BGT226 and gefitinib in non-small cell lung cancer cell lines. Katanasaka, Y., Kodera, Y., Yunokawa, M., et al.[2021]

Osimertinib, taken at a dose of 80 mg once daily, is effective for treating metastatic EGFR T790M-positive non-small cell lung cancer (NSCLC), with a steady state achieved by day 15, indicating consistent drug levels for optimal efficacy.

The pharmacokinetics of osimertinib show that it can be administered in a fixed-dose approach across different ethnicities, with minimal impact from food on drug absorption, supporting its use in various formulations without changing the dosing schedule.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Osimertinib Western and Asian clinical pharmacokinetics in patients and healthy volunteers: implications for formulation, dose, and dosing frequency in pivotal clinical studies. Planchard, D., Brown, KH., Kim, DW., et al.[2022]

In a Phase 1b study involving 110 patients with advanced solid tumors, gedatolisib combined with cisplatin showed promising clinical activity in triple-negative breast cancer (TNBC), with an overall response rate of 40% in first-line treatment and 33.3% in second/third-line treatment.

The combination therapy was generally well-tolerated, with only 10% of evaluable patients experiencing dose-limiting toxicities, primarily grade 3 oral mucositis, indicating a manageable safety profile for further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase 1B open-label study of gedatolisib (PF-05212384) in combination with other anti-tumour agents for patients with advanced solid tumours and triple-negative breast cancer. Curigliano, G., Shapiro, GI., Kristeleit, RS., et al.[2023]

Icotinib is an approved treatment for non-small cell lung cancer (NSCLC) with specific epidermal growth factor receptor (EGFR) mutations, demonstrating its efficacy in targeting these mutations.

The drug also shows moderate effectiveness in other solid tumors, such as NSCLC with rare non-resistant EGFR mutations and esophageal cancer with EGFR amplification or overexpression, indicating its potential broader application in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Icotinib: efficacy in different solid tumors and gene mutations. Zhao, Q., Cheng, J., Chen, P., et al.[2021]

References

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

A phase i study of ixazomib and erlotinib in patients with advanced solid tumors. [2022]

2. Spain pubmed.ncbi.nlm.nih.gov

The epidermal growth factor receptor pathway and its inhibition as anticancer therapy. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Axitinib, a novel anti-angiogenic drug with promising activity in various solid tumors. [2018]

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

Epidermal growth factor receptor inhibitors in development for the treatment of non-small cell lung cancer. [2018]

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

Pyrotinib: First Global Approval. [2019]

6. Ireland pubmed.ncbi.nlm.nih.gov

Synergistic anti-tumor effects of a novel phosphatidyl inositol-3 kinase/mammalian target of rapamycin dual inhibitor BGT226 and gefitinib in non-small cell lung cancer cell lines. [2021]

7. Germany pubmed.ncbi.nlm.nih.gov

Osimertinib Western and Asian clinical pharmacokinetics in patients and healthy volunteers: implications for formulation, dose, and dosing frequency in pivotal clinical studies. [2022]

8. England pubmed.ncbi.nlm.nih.gov

A Phase 1B open-label study of gedatolisib (PF-05212384) in combination with other anti-tumour agents for patients with advanced solid tumours and triple-negative breast cancer. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Icotinib: efficacy in different solid tumors and gene mutations. [2021]