ACR-368 + Gemcitabine for Head and Neck Cancer

Overseen By Kara Hoffman

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: H. Lee Moffitt Cancer Center and Research Institute

Disqualifiers: Brain metastases, Cardiovascular disease, Pregnancy, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 24 months

43 Participants Needed

Trial Summary

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

The trial protocol does not specify if you must stop taking your current medications. However, you should not have had any prior systemic therapy for 4 weeks before starting the study treatment.

What data supports the idea that ACR-368 + Gemcitabine for Head and Neck Cancer is an effective drug?

The available research shows that Gemcitabine, when tested alone, did not show significant effectiveness in treating head and neck cancer, as there were no objective treatment responses and the median survival was only 6 months. However, in preclinical studies, Gemcitabine showed a significant antitumor effect in human tumor models, performing better than other drugs like cisplatin and methotrexate. This suggests potential when combined with other treatments, but specific data on ACR-368 + Gemcitabine for head and neck cancer is not provided in the available research. ^{1 2 3 4 5}

What safety data is available for ACR-368 and Gemcitabine in head and neck cancer treatment?

The safety data for Gemcitabine (Gemzar) in head and neck cancer treatment includes findings from a phase II trial where 26 patients experienced nausea and vomiting, with infrequent grade 3 or 4 hematologic toxicities. Two patients developed neutropenic infections, and one patient had fatal liver failure, possibly due to liver metastases or infection. Gemcitabine was not considered active enough as monotherapy for further evaluation in this disease population. Additionally, Gemcitabine has been studied in combination with cisplatin, showing promising overall survival rates in recurrent/metastatic squamous cell carcinoma of the head and neck. However, specific safety data for ACR-368 (Prexasertib, LY-2606368) in combination with Gemcitabine for head and neck cancer is not detailed in the provided research. ^{1 2 4 5 6}

Is the drug ACR-368, Gemcitabine a promising treatment for head and neck cancer?

Yes, Gemcitabine shows promise as a treatment for head and neck cancer. It has demonstrated significant antitumor effects in preclinical studies and has been effective when combined with other treatments like radiotherapy. It also has a broad anti-tumor effect and a favorable safety profile, making it a good candidate for further clinical trials. ^{1 2 7 8 9}

What is the purpose of this trial?

The purpose of the study is to determine the activity and safety of ACR-368 (prexasertib) in combination with gemcitabine in participants with Head and Neck Squamous Cell Carcinoma (HNSCC). Participants will receive the study drugs ACR-368 and a low dose of gemcitabine once every 2 weeks in 4-week cycles and will continue on treatment unless the disease deteriorates.

Research Team

Christine Chung, MD

Principal Investigator

Moffitt Cancer Center

Eligibility Criteria

This trial is for individuals with recurrent or metastatic Head and Neck Squamous Cell Carcinoma (HNSCC). Participants should not have had previous chemotherapy for their recurrent/metastatic disease, must be able to receive medication intravenously, and have measurable disease as per RECIST criteria. Key exclusions include prior treatment with ACR-368 or gemcitabine in the metastatic setting, active infections, significant cardiovascular disease, or other serious medical conditions.

Inclusion Criteria

* Patient (or a legally authorized representative) must understand and voluntarily sign informed consent prior to any study-related assessments/procedures being conducted.

* Must be able and willing to comply with the study visit schedule and protocol requirements.

* Must have sufficient archived tumor tissue available for p16 immunohistochemistry (IHC) staining if the status is unknown. HPV status determined by HPV DNA sequencing, HPV DNA/RNA in situ hybridization, or equivalent assays using tumor tissue or cell free HPV DNA testing or equivalent using blood-based assays are also acceptable. If there is a discrepancy between p16 IHC and HPV detection assay results, HPV detection assay result will be used.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ACR-368 and low dose gemcitabine every 2 weeks in 4-week cycles

Up to 24 months

Bi-weekly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• ACR-368
• Gemcitabine

Trial Overview The study is testing the effectiveness and safety of a combination therapy: ACR-368 (prexasertib) alongside low dose gemcitabine. Patients will be treated every two weeks over four-week cycles. The goal is to see how well this combo works against HNSCC compared to standard treatments.

Participant Groups

Group I: Cohort B (p16/HPV-pos) Experimental Treatment 2 Interventions

Participants with p16/HPV-positive R/M HNSCC will be assigned to Cohort B. Participants will be administered lead-in low dose gemcitabine (LDG) 10 mg/m2 IV Day -7 (+/- 3 days, before Cycle 1 only) followed by ACR-368 105 mg/m2 IV every 2 weeks and LDG 10 mg/m2 every 2 weeks until discontinuation due to disease progression, intolerability, or consent withdrawal. When delay or discontinuation of the treatment is necessary, both ACR-368 and LDG will be delayed or discontinued together.

Group II: Cohort A (p16/HPV-neg) Experimental Treatment 2 Interventions

Participants with p16/HPV-negative recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) will be assigned to Cohort A. Participants will be administered lead-in low dose gemcitabine (LDG) 10 mg/m2 IV Day -7 (+/- 3 days, before Cycle 1 only) followed by ACR-368 105 mg/m2 IV every 2 weeks and LDG 10 mg/m2 every 2 weeks until discontinuation due to disease progression, intolerability, or consent withdrawal. When delay or discontinuation of the treatment is necessary, both ACR-368 and LDG will be delayed or discontinued together.

Who Is Running the Clinical Trial?

H. Lee Moffitt Cancer Center and Research Institute

Lead Sponsor

Trials

576

Recruited

145,000+

Acrivon Therapeutics

Industry Sponsor

Trials

3

Recruited

520+

Findings from Research

In a phase II trial involving 26 patients with recurrent or metastatic squamous cell carcinoma of the head and neck, gemcitabine was administered weekly, but no objective treatment responses were observed, indicating limited efficacy in this patient population.

While gemcitabine was generally well-tolerated, with infrequent severe hematologic toxicities, one patient experienced fatal liver failure, suggesting that while the drug has a manageable safety profile, its effectiveness as a monotherapy is insufficient for further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of gemcitabine in patients with recurrent or metastatic squamous cell carcinoma of the head and neck: a Southwest Oncology Group phase II study. Samlowski, WE., Gundacker, H., Kuebler, JP., et al.[2022]

2',2'-Difluorodeoxycytidine (dFdCyd, Gemcitabine) demonstrated significant antitumor effects in human tumor xenografts of squamous cell carcinoma of the head and neck, with some tumors showing no regrowth for 90 days after treatment.

When compared to standard chemotherapy drugs like cisplatin and methotrexate, dFdCyd was found to be more effective at equitoxic doses, suggesting it could be a promising candidate for clinical trials in patients with this type of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical in vivo activity of 2',2'-difluorodeoxycytidine (Gemcitabine) against human head and neck cancer. Braakhuis, BJ., van Dongen, GA., Vermorken, JB., et al.[2022]

The combination of gemcitabine (GEM) and vinorelbine (VNB) showed a 25% overall response rate in 24 patients with recurrent squamous cell head and neck carcinoma, indicating some efficacy, particularly in patients with favorable prognostic characteristics.

Neutropenia was the most common side effect, affecting 92% of patients, with half experiencing severe cases (grade 3-4), highlighting the treatment's toxicity profile. Additionally, the combination did not improve outcomes compared to VNB alone and did not alter the pharmacokinetics of either drug.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gemcitabine and vinorelbine in recurrent head and neck cancer: pharmacokinetic and clinical results. Airoldi, M., Cattel, L., Cortesina, G., et al.[2022]

In a clinical trial involving 38 patients with locally advanced head and neck squamous cell cancer, the combination of apatinib and S-1 as an induction therapy achieved a remarkable objective response rate of 97.4%, indicating high efficacy in shrinking tumors before further treatment.

While the treatment was associated with manageable adverse effects like hypertension and hand-foot syndrome, it did not demonstrate a significant survival benefit, suggesting that while effective in initial response, further research is needed to improve long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and feasibility of Apatinib and S-1 as a novel oral induction therapy in locally advanced head and neck squamous cell carcinoma: an exploratory phase 2 open-label, single-arm trial. Jiang, W., Li, R., Zhang, L., et al.[2023]

In a study of 40 male patients with recurrent/metastatic squamous cell carcinoma of the head and neck, the combination of gemcitabine and cisplatin showed a 30% overall response rate and a 53.3% disease control rate, indicating its efficacy as a first-line treatment.

The treatment was associated with significant side effects, including severe leukopenia in 65% of patients and anemia in 27.5%, highlighting the need for careful monitoring of patients during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Promising overall survival of patients with recurrent/metastatic squamous cell carcinoma of head and neck receiving gemcitabine plus cisplatin treatment: report of a multi-center phase II study. Yang, MH., Chang, PM., Tzeng, CH., et al.[2022]

The combination of toripalimab (a PD-1 inhibitor) with gemcitabine and cisplatin (GP) in 23 patients with locally advanced head and neck squamous cell carcinoma showed a promising overall response rate of 45% and a 100% R0 resection rate after surgical resection.

The treatment was generally safe, with a 43.5% incidence of treatment-related adverse events, but no surgical delays were reported, indicating that this neoadjuvant approach is feasible for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant toripalimab combined with gemcitabine and cisplatin in resectable locally advanced head and neck squamous cell carcinoma (NeoTGP01): An open label, single-arm, phase Ib clinical trial. Huang, X., Liu, Q., Zhong, G., et al.[2022]

In a study of 28 patients with advanced squamous cell carcinoma of the head and neck, gemcitabine-based induction chemotherapy followed by concurrent gemcitabine and radiotherapy resulted in a significant treatment response, with 60.7% achieving complete response after treatment.

The treatment was associated with manageable toxicity, with acute side effects like dysphagia and stomatitis occurring in a notable percentage of patients, indicating that while effective, further optimization of the treatment regimen is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gemcitabine-based induction chemotherapy and concurrent with radiation in advanced head and neck cancer. El Deen, DA., Toson, EA., El Morsy, SM.[2022]

In a small phase-II study involving 10 heavily pre-treated patients with recurrent squamous-cell carcinoma of the head and neck, gemcitabine showed a response rate of 37.5%, with one complete remission and two partial remissions observed.

Gemcitabine demonstrated a favorable safety profile, with low incidence of severe hematological toxicity and manageable side effects, suggesting it could be a promising treatment option for patients who have not responded to other chemotherapy agents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gemcitabine in the treatment of advanced head and neck cancer. Raguse, JD., Gath, HJ., Bier, J., et al.[2022]

The combination of weekly gemcitabine (GEM) with conventional radiotherapy (RT) in 26 patients with locally advanced squamous cell carcinoma of the head and neck showed high efficacy, with all evaluable patients responding to treatment (50% complete response, 50% partial response).

While the treatment was feasible and resulted in promising long-term local control, it also caused significant acute non-hematologic toxicities, including severe stomatitis (85% of patients) and pharyngitis/esophagitis (81%), which impacted normal food intake and required feeding tubes for 80% of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II feasibility study of concurrent radiotherapy and gemcitabine in chemonaive patients with squamous cell carcinoma of the head and neck: long-term follow up data. Specenier, PM., Van den Weyngaert, D., Van Laer, C., et al.[2022]

References

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

Evaluation of gemcitabine in patients with recurrent or metastatic squamous cell carcinoma of the head and neck: a Southwest Oncology Group phase II study. [2022]

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

Preclinical in vivo activity of 2',2'-difluorodeoxycytidine (Gemcitabine) against human head and neck cancer. [2022]

3. Greece pubmed.ncbi.nlm.nih.gov

Gemcitabine and vinorelbine in recurrent head and neck cancer: pharmacokinetic and clinical results. [2022]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Efficacy and feasibility of Apatinib and S-1 as a novel oral induction therapy in locally advanced head and neck squamous cell carcinoma: an exploratory phase 2 open-label, single-arm trial. [2023]

5. Germany pubmed.ncbi.nlm.nih.gov

Promising overall survival of patients with recurrent/metastatic squamous cell carcinoma of head and neck receiving gemcitabine plus cisplatin treatment: report of a multi-center phase II study. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Neoadjuvant toripalimab combined with gemcitabine and cisplatin in resectable locally advanced head and neck squamous cell carcinoma (NeoTGP01): An open label, single-arm, phase Ib clinical trial. [2022]

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

Gemcitabine-based induction chemotherapy and concurrent with radiation in advanced head and neck cancer. [2022]

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

Gemcitabine in the treatment of advanced head and neck cancer. [2022]

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

Phase II feasibility study of concurrent radiotherapy and gemcitabine in chemonaive patients with squamous cell carcinoma of the head and neck: long-term follow up data. [2022]