Zotatifin for Solid Tumors

(Zotatifin Trial)

Recruiting at 17 trial locations

Overseen By Mark Densel

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Effector Therapeutics

Must be taking: CDK4/6 inhibitors

Disqualifiers: KRAS G12C mutations, others

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

Compensation: Varies

Number of Visits: Unknown

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment called Zotatifin (also known as eFT226), targeting advanced solid tumors such as certain breast and lung cancers. The goal is to assess the safety and effectiveness of Zotatifin, especially in combination with other medications. The trial includes different groups, with some receiving Zotatifin alone and others alongside standard treatments. It suits individuals with breast cancer that has spread and resisted other treatments or those with lung cancer and specific genetic traits, such as certain KRAS mutations. Participants should have previously tried several treatments without success. As a Phase 1/Phase 2 trial, this research aims to understand how the treatment works in people and measure its effectiveness in an initial, smaller group.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that zotatifin, the treatment being tested in this trial, has shown promise in early studies. It proved effective in models of solid tumors, including those with specific gene changes like HER2 and KRAS. In ongoing studies, patients have received zotatifin with other treatments, suggesting it may enhance the effectiveness of other cancer therapies.

While zotatifin is still under evaluation for safety and effectiveness, the FDA has granted fast track status to one of its combinations for certain types of breast cancer. This indicates the FDA sees potential in zotatifin, but more data is needed to confirm its safety and benefits.

In this trial, zotatifin is tested in various combinations. Previous patients have generally tolerated these treatments, but as with any medical study, side effects can occur. Always discuss any concerns with the trial team to determine if this treatment is suitable. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about eFT226, known as Zotatifin, because it offers a fresh approach to treating solid tumors, especially breast cancer. Unlike standard treatments that often target hormone receptors or HER2, Zotatifin works by inhibiting eukaryotic translation initiation factor 4A (eIF4A), a key player in the protein synthesis pathway. This unique mechanism may effectively slow tumor growth by blocking the production of cancer-promoting proteins. Additionally, Zotatifin is administered intravenously in carefully controlled cycles, which might allow for more precise dosing and potentially fewer side effects compared to conventional therapies. These features make Zotatifin a promising option for patients and a focus of excitement within the research community.

What evidence suggests that this trial's treatments could be effective for solid tumors?

Research has shown that Zotatifin, also known as eFT226, may help treat certain solid tumors. In early tests, it effectively targeted tumors with specific gene changes such as HER2, FGFR1/2, and KRAS. In this trial, participants may receive Zotatifin as monotherapy or in combination with other drugs. For instance, one arm of the trial combines Zotatifin with abemaciclib and fulvestrant, which, in previous studies, resulted in a 21% response rate in patients who had already undergone many treatments. These early findings suggest that Zotatifin could be a helpful treatment option for certain types of cancer. ^{1 2 6 7 8}

Who Is on the Research Team?

Douglas Warner, MD

Principal Investigator

EFFECTOR Therapeutics, Inc.

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• eFT226

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04092673

NCT04092673 | Study of eFT226 in Subjects With Selected ... Preclinical efficacy testing of eFT226 demonstrates activity across models of solid tumor cancers with amplifications in HER2, FGFR1/2 and mutations in KRAS ...

2. clin.larvol.com clin.larvol.com/trial-detail/NCT04092673

Study of eFT226 in Subjects With Selected Advanced Solid ... "In the ongoing Phase 1/2 dose escalation and expansion trial of zotatifin in multiple solid tumors, patients have been dosed in two recently opened combination ...

3. biospace.com biospace.com/effector-therapeutics-reports-positive-interim-results-in-zotatifin-eft226-phase-1-2-clinical-trial-at-asco-2022-showing-safety-and-tolerability-and-initial-signals-of-clinical-activity

eFFECTOR Therapeutics Reports Positive Interim Results ... Patients treated with zotatifin demonstrated reductions in the expression of key oncogenic drivers, including Cyclin E1 and Bcl-2. The most ...

4. onclive.com onclive.com/view/zotatifin-triplet-shows-promising-activity-low-toxicity-in-heavily-pretreated-er-breast-cancer

Zotatifin Triplet Shows Promising Activity, Low Toxicity in ... The triplet combination of zotatifin, abemaciclib, and fulvestrant demonstrated a confirmed overall response rate of 21% in heavily pretreated ...

5. targetedonc.com targetedonc.com/view/zotatifin-with-fulvestrant-and-abemaciclib-shows-favorable-activity-in-er-breast-cancer

Zotatifin With Fulvestrant and Abemaciclib Shows ... The study is evaluating the safety, pharmacokinetics (PK), pharmacodynamics, and antitumor activity of zotatifin in patients with KRAS-mutated ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8663026/

Zotatifin, an eIF4A-Selective Inhibitor, Blocks Tumor Growth in ... Combination of zotatifin with PI3K or AKT inhibitors was beneficial across RTK-driven cancer models by blocking RTK-driven resistance mechanisms demonstrating ...

7. targetedonc.com targetedonc.com/view/zotatifin-triplet-gains-fda-fast-track-status-in-er-her2--breast-cancer

Zotatifin Triplet Gains FDA Fast Track Status in ER+/HER2 The FDA has granted a fast track designation to the combination of zotatifin, fulvestrant, and abemaciclib as a second- or third-line treatment for adult ...

8. clinicaltrials.stanford.edu clinicaltrials.stanford.edu/trials/s/NCT04092673.html

Study of eFT226 in Subjects With Selected Advanced Solid ... This clinical trial is a Phase 1-2, open-label, sequential-group, dose-escalation and cohort-expansion study evaluating the safety, pharmacokinetics (PK), ...