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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the combination of two drugs, ACR-368 (also known as Prexasertib or LY-2606368) and gemcitabine (also known as Gemzar), to evaluate their effectiveness and safety in treating head and neck squamous cell carcinoma (HNSCC). The study targets participants with either p16/HPV-positive or p16/HPV-negative cancer. Suitable candidates include those with recurrent or metastatic head and neck cancer who have previously received PD-1/PD-L1 inhibitors or chemotherapy. Participants will receive the study drugs every two weeks, provided their condition does not worsen. As a Phase 2 trial, this research aims to measure the treatment's effectiveness in an initial, smaller group, offering a chance to contribute to significant findings.

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.

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

Research has shown that ACR-368 (also known as prexasertib) combined with a low dose of gemcitabine has been studied for safety. Previous patients found the treatment to be mostly well-tolerated, with side effects aligning with known profiles of these drugs.

For ACR-368, studies indicate it usually causes mild to moderate side effects, such as low blood counts, tiredness, and nausea. Gemcitabine, already approved by the FDA for other cancers, can cause side effects like low blood counts, nausea, and rash, but these are usually manageable.

Overall, while both drugs can cause some side effects, they are generally considered safe at the doses used in the studies. Participants considering joining the trial should consult their healthcare provider to understand what to expect. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about ACR-368 with Gemcitabine for head and neck cancer because it combines a novel agent with a well-known chemotherapy drug to potentially enhance effectiveness. Unlike the standard treatments like cisplatin or cetuximab, which primarily focus on DNA damage or epidermal growth factor receptors, ACR-368 targets unique cancer cell mechanisms, possibly offering a new pathway to tackle tumors. This combination could improve outcomes for patients with recurrent or metastatic head and neck cancers, especially those with different HPV statuses, by tailoring approaches specific to the cancer's characteristics.

What evidence suggests that this trial's treatments could be effective for head and neck cancer?

This trial will evaluate the combination of ACR-368 and low-dose gemcitabine for treating head and neck squamous cell carcinoma (HNSCC). Participants in Cohort A, with p16/HPV-negative HNSCC, and Cohort B, with p16/HPV-positive HNSCC, will receive this combination therapy. Research has shown that ACR-368, when combined with a low dose of gemcitabine, may help treat HNSCC. ACR-368 is a drug that inhibits certain proteins from aiding cancer cells in repairing their DNA, leading to cell death. Previous studies found that ACR-368 alone can be effective against advanced squamous cell carcinoma. Gemcitabine is a chemotherapy drug that halts cancer cell growth by damaging their DNA. Together, these drugs aim to kill more cancer cells by blocking their repair and growth. Early results suggest this combination could be effective, but further research is needed to confirm its benefits. ^{3 6 7 8 9}

Who Is on the Research Team?

Christine Chung, MD

Principal Investigator

Moffitt Cancer Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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 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]

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]

Citations

1. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2024-08120

ACR-368 in Combination with Low Dose Gemcitabine for ... This phase II trial tests how well ACR-368 in combination with low dose gemcitabine works in treating patients with head and neck squamous cell carcinoma ...

2. researchgate.net researchgate.net/publication/392299963_A_phase_II_study_of_ACR-368_and_low_dose_gemcitabine_combination_therapy_in_patients_with_recurrent_andor_metastatic_head_and_neck_squamous_cell_carcinoma

A phase II study of ACR-368 and low dose gemcitabine ... ACR-368 (prexasertib) is a potent, selective CHK1/2 inhibitor which impairs DNA damage repair (DDR) and induces cancer cell apoptosis. ACR-368 ...

3. healthscout.app healthscout.app/trial_match/view_trial/NCT06597565/?back=/trial_match/drug/3649/%3Fback%3D/trial_match/drugs/

Trial: A Phase II Study of ACR-368 and Low Dos… - HealthScout A Phase II Study of ACR-368 and Low Dose Gemcitabine Combination Therapy in Patients With Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6050086/

Evaluation of Prexasertib, a Checkpoint Kinase 1 Inhibitor, in a ... Prexasertib, a checkpoint kinase 1 inhibitor, demonstrated single-agent activity in patients with advanced squamous cell carcinoma (SCC) in the dose-escalation ...

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.TPS6109

HexAgon-HN: Phase 2/3, randomized study of the ... A phase 2/3, randomized study evaluating INBRX-106 + pembro vs pembro alone as first-line treatment for R/M HNSCC with a PD-L1 CPS of ≥20.

6. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.TPS6110

A phase II study of ACR-368 and low dose gemcitabine ... This is a multi-center, parallel-arm, open-label, phase II trial evaluating combined ACR-368 with LDG in patients with R/M HNSCC.

7. connect.careboxhealth.com connect.careboxhealth.com/en-US/trial/listing/532818

A Phase II Study of ACR-368 and Low Dose Gemcitabine in R ... 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 ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6247064/

Dose‐finding study of the checkpoint kinase 1 inhibitor ... In conclusion, the overall safety findings in this study were consistent with the known safety profile for prexasertib, and tolerability at the recommended dose ...

9. sciencedirect.com sciencedirect.com/topics/medicine-and-dentistry/prexasertib

Prexasertib - an overview Prexasertib, also known as ACR-368, is a CHK-1 inhibitor that is prioritized for clinical trials in treating DSRCT and neuroblastoma due to its activity ...