ABBV-CLS-484 + PD-1/VEGFR Inhibitors for Cancer

Recruiting at 58 trial locations

Overseen By ABBVIE CALL CENTER

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: AbbVie

Must not be taking: Steroids, Immune-oncology agents

Disqualifiers: Brain metastases, Hepatitis, HIV, others

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

Compensation: Varies

Number of Visits: Unknown

248 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment called ABBV-CLS-484 (also known as Osunprotafib or AC484) for individuals with advanced solid tumors. The main goal is to determine a safe and effective dose, whether used alone or with other cancer-fighting drugs, such as Programmed Cell Death-1 (PD-1) Inhibitors and Vascular Endothelial Growth Factor Receptor (VEGFR) Tyrosine Kinase Inhibitors (TKIs). The trial seeks participants with advanced cancers like lung, head and neck, or kidney cancer who have tried other treatments without success. This study may suit those battling these cancers and seeking new options. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive it.

Do I need to stop my current medications to join the 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 to get a clear answer based on your specific situation.

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

Research has shown that ABBV-CLS-484 is generally safe when used alone. One study found that doses up to 150 mg/kg daily did not cause major safety issues, with most participants not experiencing serious side effects at this dose.

When combined with a PD-1 inhibitor, ABBV-CLS-484 remains safe. The research indicated that side effects were manageable.

Specific information about side effects when ABBV-CLS-484 is combined with a VEGFR inhibitor is not yet available. These studies are in early stages, so researchers are carefully monitoring participants to determine the safest dose.

In summary, current research suggests that ABBV-CLS-484 is safe when taken alone or with a PD-1 inhibitor. The safety of combining it with a VEGFR inhibitor is still under investigation. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about ABBV-CLS-484 because it offers a fresh approach to treating certain advanced cancers. Unlike the standard treatments that typically involve chemotherapy, radiation, or existing targeted therapies like PD-1/PD-L1 inhibitors, ABBV-CLS-484 works by combining with VEGFR Tyrosine Kinase Inhibitors or PD-1 inhibitors to precisely target cancer cells. This combination aims to enhance the body's immune response while directly interfering with pathways that tumors use to grow. By focusing on these novel mechanisms, ABBV-CLS-484 holds promise for patients whose cancers have become resistant to current treatments.

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

Research has shown that ABBV-CLS-484 may help fight cancer by boosting the body's immune system. This drug activates the area around the tumor, triggering important immune cells called natural killer cells and CD8+ T cells. In studies, these cells became more effective at destroying cancer cells. In this trial, some participants will receive ABBV-CLS-484 with a PD-1 inhibitor, which may help overcome resistance to treatments targeting PD-1, a protein that allows cancer cells to hide from the immune system. Other participants will receive ABBV-CLS-484 with a VEGFR inhibitor, which might enhance effectiveness by interfering with cancer cell growth. These findings suggest that ABBV-CLS-484 could offer a new way to treat various advanced cancers. ^{1 3 6 7 8}

Who Is on the Research Team?

ABBVIE INC.

Principal Investigator

AbbVie

Are You a Good Fit for This Trial?

This trial is for adults with advanced solid tumors who've tried at least one cancer therapy without success. They must be physically capable of daily activities, weigh over 35 kg, and have a life expectancy of at least 12 weeks. Certain conditions like uncontrolled high blood pressure or recent severe illnesses exclude participation.

Inclusion Criteria

I am able to get out of my bed or chair and move around.

Laboratory values meeting protocol criteria.

QT interval corrected for heart rate < 470 msec (using Fridericia's correction), and no clinically significant electrocardiographic findings.

Exclusion Criteria

I currently have an active COVID-19 infection.

I do not have ongoing severe numbness or pain in my hands or feet.

I haven't needed systemic treatment for an autoimmune disease in the last 2 years, except for thyroid issues, skin depigmentation, or severe allergies.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Monotherapy Dose Escalation

ABBV-CLS-484 is administered alone in escalating dose levels to eligible subjects with advanced solid tumors

Up to 6 weeks

Combination Dose Escalation

ABBV-CLS-484 is administered at escalating dose levels in combination with a PD-1 targeting agent or with a VEGFR TKI to eligible subjects with advanced solid tumors

Up to 9 weeks

Dose Expansion

ABBV-CLS-484 is administered at the recommended dose as monotherapy and in combination with a PD-1 targeting agent or VEGFR TKI in subjects with specific types of advanced or metastatic tumors

Up to 9 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• ABBV-CLS-484
• Programmed Cell Death-1 (PD-1) Inhibitor
• Vascular Endothelial Growth Factor Receptor (VEGFR) Tyrosine Kinase Inhibitor (TKI)

Trial Overview ABBV-CLS-484's safety and effectiveness are being tested alone or with other drugs targeting PD-1 or VEGFR in patients with specific cancers including head and neck squamous cell carcinoma, non-small cell lung cancer, and renal cell carcinoma. The study has three parts: dose escalation for monotherapy and combination therapy, followed by dose expansion.

How Is the Trial Designed?

Group I: Monotherapy Expansion Experimental Treatment 1 Intervention

ABBV-CLS-484 will be administered at the determined recommended dose in subjects with locally advanced or metastatic, relapsed or refractory head and neck squamous cell carcinoma (HNSCC), relapsed or refractory non-small cell lung cancer (NSCLC), and advanced clear cell renal cell carcinoma (ccRCC)

Group II: Monotherapy Dose Escalation Experimental Treatment 1 Intervention

ABBV-CLS-484 will be administered as a monotherapy in subjects with solid tumors

Group III: Combination Expansion with PD-1 Inhibitor Experimental Treatment 3 Interventions

ABBV-CLS-484 will be administered at the determined recommended dose in combination with Programmed Cell Death-1 Inhibitor in subjects with locally advanced or metastatic, HNSCC, NSCLC, MSI-H tumors refractory to PD-1/PD-L1, and advanced ccRCC.

Group IV: Combination Expansion Experimental Treatment 3 Interventions

ABBV-CLS-484 will be administered at the determined recommended dose in combination with VEGFR TKI in subjects with locally advanced or metastatic, HNSCC, NSCLC, MSI-H tumors refractory to PD-1/PD-L1, and advanced ccRCC.

Group V: Combination Dose Escalation with VEGFR TKI Experimental Treatment 3 Interventions

ABBV-CLS-484 will be administered in combination with a Vascular Endothelial Growth Factor Receptor (VEGFR) Tyrosine Kinase Inhibitor (TKI) in subjects with solid tumors

Group VI: Combination Dose Escalation with PD-1 Inhibitor Experimental Treatment 2 Interventions

ABBV-CLS-484 will be administered in combination with Programmed Cell Death-1 Inhibitor in subjects with solid tumors

Who Is Running the Clinical Trial?

AbbVie

Lead Sponsor

Trials

1,079

Recruited

535,000+

Founded

2013

Headquarters

North Chicago, USA

Known For

Immunology treatments

Top Products

Humira (adalimumab), Skyrizi (risankizumab), Rinvoq (upadacitinib)

Dr. Roopal Thakkar

AbbVie

Chief Medical Officer since 2023

MD from Wayne State University School of Medicine

Robert A. Michael

AbbVie

Chief Executive Officer

Bachelor's degree in Finance from the University of Illinois

Calico Life Sciences LLC

Industry Sponsor

Trials

11

Recruited

960+

Published Research Related to This Trial

In a study involving six patients with EGFR-mutated lung adenocarcinoma, the combination of osimertinib and ramucirumab was found to be generally safe, with only one case of dose-limiting toxicity (grade 3 appetite loss) and no other severe adverse events reported.

Five out of six patients showed a partial response to the treatment, with a median progression-free survival of 9.2 months for those with the EGFR T790M mutation, suggesting promising efficacy that warrants further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase Ib Study of Osimertinib Plus Ramucirumab in Japanese Lung Cancer Patients With EGFR Mutation. Akamatsu, H., Ozawa, Y., Oyanagi, J., et al.[2023]

A retrospective analysis of adverse events related to PD-1/PD-L1 inhibitors revealed a significant association between Pembrolizumab and hepatitis B reactivation (HBVr), with a reporting odds ratio of 2.32, indicating a higher risk compared to other treatments.

No cases of HBVr were reported with Ipilimumab or Avelumab, suggesting that not all immune checkpoint inhibitors carry the same risk, highlighting the need for further prospective studies to confirm these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hepatitis B Virus Reactivation in Cancer Patients Treated With Immune Checkpoint Inhibitors. Burns, EA., Muhsen, IN., Anand, K., et al.[2023]

In a study of 46 patients with advanced NSCLC and Del19-EGFR, afatinib showed a high objective response rate of 78.2% and a median progression-free survival of 20.5 months, indicating its efficacy as a first-line treatment.

Older patients (≥70 years) experienced similar benefits from afatinib as younger patients, with manageable side effects, although they required more dose reductions, suggesting afatinib is a viable treatment option for older adults with this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world data with afatinib in Spanish patients with treatment-naïve non-small-cell lung cancer harboring exon 19 deletions in epidermal growth factor receptor (Del19 EGFR): Clinical experience of the Galician Lung Cancer Group. Agraso, S., Lázaro, M., Firvida, XL., et al.[2022]

Combining the PD-1 inhibitor sintilimab with the anti-angiogenic drug anlotinib significantly improved the disease control rate (DCR) in patients with non-small cell lung cancer (NSCLC) compared to those receiving either treatment alone.

This combination therapy also prolonged progression-free survival (PFS) without increasing the incidence of immune-related adverse reactions, suggesting it is a safe and effective treatment option for NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of PD-1 inhibitor combined with anti-angiogenic drugs on efficacy and immune function of non-small cell lung cancer. Zhang, Y., Zhu, T., Wang, Q., et al.[2022]

In a study of 46 lung adenocarcinoma patients treated with immune checkpoint inhibitors (ICI) and angiogenic inhibitors, the overall response rate was 8.7% and the disease control rate was 50%, indicating some effectiveness of this combination therapy.

The median progression-free survival (PFS) was 2.9 months, with a notable finding that patients who developed hypertension during treatment had a longer PFS, suggesting a potential link between hypertension and treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune checkpoint inhibitors combined with angiogenic inhibitors in the treatment of locally advanced or metastatic lung adenocarcinoma patients. Feng, Y., Tang, L., Wang, H., et al.[2023]

In patients with relapsed small-cell lung cancer (SCLC), the combination of anlotinib and PD-1 inhibitor significantly improved progression-free survival (PFS) compared to PD-1 inhibitor alone, with PFS of 5.0 months versus 3.0 months.

For relapsed non-small-cell lung cancer (NSCLC), the same combination therapy resulted in a higher objective response rate and longer PFS compared to monotherapy, indicating its potential as an effective treatment option with manageable toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anlotinib combined with PD-1 blockade for the treatment of lung cancer: a real-world retrospective study in China. Zhang, X., Zeng, L., Li, Y., et al.[2021]

In a phase II trial involving 28 women with persistent or recurrent cervical cancer, brivanib showed a median progression-free survival (PFS) of 3.2 months, with 25% of patients achieving a PFS greater than 6 months, indicating some efficacy in this difficult-to-treat population.

Brivanib was generally well tolerated, but notable grade 3 adverse events included hypertension and anemia, highlighting the need for careful monitoring of side effects during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II evaluation of brivanib in the treatment of persistent or recurrent carcinoma of the cervix: An NRG Oncology/Gynecologic Oncology Group study. Chan, JK., Deng, W., Higgins, RV., et al.[2022]

The combination of nivolumab and ipilimumab as neoadjuvant therapy for resectable non-small cell lung cancer (NSCLC) was found to be feasible, but the study was terminated early due to significant treatment-related adverse events (TRAEs), with 67% of patients experiencing some form of toxicity.

Despite the challenges, two patients achieved a pathologic complete response (pCR) and remained disease-free for over 24 months, suggesting that further research is needed to identify biomarkers that could predict which patients are more likely to benefit from this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant nivolumab plus ipilimumab in resectable non-small cell lung cancer. Reuss, JE., Anagnostou, V., Cottrell, TR., et al.[2021]

The combination of regorafenib and anti-PD1 therapy significantly improved survival in mice with hepatocellular carcinoma (HCC), with the effectiveness increasing with higher doses of regorafenib.

This combination therapy works by normalizing tumor blood vessels and enhancing the infiltration and activation of CD8 T-cells in the tumor, which is mediated by increased levels of CXCL10, a key factor for T-cell recruitment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regorafenib combined with PD1 blockade increases CD8 T-cell infiltration by inducing CXCL10 expression in hepatocellular carcinoma. Shigeta, K., Matsui, A., Kikuchi, H., et al.[2021]

The combination of nivolumab (10 mg/kg) with standard chemotherapy was well tolerated in patients with advanced non-small-cell lung cancer (NSCLC), with only one case of dose-limiting toxicity observed among 24 patients across four treatment arms.

Nivolumab combined with chemotherapy showed promising antitumor activity, with median progression-free survival ranging from 3.15 months to 9.63 months, indicating its potential effectiveness in treating advanced NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of nivolumab and standard chemotherapy drug combination in patients with advanced non-small-cell lung cancer: a four arms phase Ib study. Kanda, S., Goto, K., Shiraishi, H., et al.[2022]

In a study of 85 patients with driver gene-negative stage IV lung adenocarcinoma, combining bevacizumab with pembrolizumab significantly improved the overall effective rate (48.89% vs. 27.50%) and disease control rate (93.33% vs. 72.50%) compared to the control group receiving only chemotherapy and pembrolizumab.

The combination treatment also led to a significant increase in cellular immune function and improved quality of life, with a median progression-free survival (PFS) of 13.00 months for the combination group compared to 9.00 months for the control group, indicating enhanced short-term therapeutic effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Study on the Efficacy of Bevacizumab in Combination with Pembrolizumab on Cellular Immune Function in the Treatment of Driver Gene-Negative Stage IV Lung Adenocarcinoma. Gong, J., Gu, J., Jiang, L., et al.[2022]

Blocking the PD-1 pathway with specific drugs has shown clinical effectiveness in treating advanced cancers like melanoma and lung cancer, by enhancing the body's anti-tumor immune response.

These PD-1/PD-L1 blocking drugs have a manageable safety profile, making them suitable for outpatient treatment and potential use in combination therapies, with ongoing research focused on identifying biomarkers for better patient selection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antagonists of PD-1 and PD-L1 in Cancer Treatment. Lipson, EJ., Forde, PM., Hammers, HJ., et al.[2022]

In a clinical trial involving 105 patients with advanced non-small cell lung cancer (NSCLC), the combination of apatinib and camrelizumab demonstrated promising antitumor activity, with an objective response rate of 30.9% and a median overall survival of 15.5 months.

The treatment was well-tolerated with no unexpected adverse events, and it appeared particularly effective in patients with STK11/KEAP1 mutations, suggesting that this genetic profile may predict better outcomes with the combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Biomarker Analysis of Camrelizumab in Combination with Apatinib in Patients with Advanced Nonsquamous NSCLC Previously Treated with Chemotherapy. Zhou, C., Wang, Y., Zhao, J., et al.[2022]

Citations

1. nature.com nature.com/articles/s41586-023-06575-7

The PTPN2/PTPN1 inhibitor ABBV-CLS-484 unleashes ... We show that AC484 inflames the tumour microenvironment and promotes natural killer cell and CD8+ T cell function by enhancing JAK–STAT ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04777994

NCT04777994 | Study With ABBV-CLS-484 in Participants ... The study will assess the safety, PK, PD, and preliminary efficacy of ABBVCLS-484 as monotherapy and in combination with a PD-1 targeting agent or with a or ...

3. abbvieclinicaltrials.com abbvieclinicaltrials.com/study/?id=M20-431

Study With ABBV-CLS-484 in Participants With Locally ... The study will assess the safety, PK, PD, and preliminary efficacy of ABBVCLS-484 as monotherapy and in combination with a PD-1 targeting agent or with a or ...

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37794185/

The PTPN2/PTPN1 inhibitor ABBV-CLS-484 unleashes potent ... We show that AC484 inflames the tumour microenvironment and promotes natural killer cell and CD8 + T cell function by enhancing JAK-STAT signalling and ...

5. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/2742/531568/The-First-in-Class-PTPN2-1-Inhibitor-Abbv-CLS-484

The First-in-Class PTPN2/1 Inhibitor Abbv-CLS-484 Disrupts ... The first-in-class PTPN2/1 inhibitor AC484 showed a great anti-tumor effect against ALK+ ALCL by disrupting mitochondrial function and mitophagy.

6. caymanchem.com caymanchem.com/product/40169/abbv-cls-484-hydrochloride?srsltid=AfmBOoqQPZ-0CLTTPb5hx06998LE-fPZQrybGDsHgzYPV8dYDaFuhBwB

ABBV-CLS-484 (hydrochloride) (Osunprotafib) ABBV-CLS-484 is a dual inhibitor of protein tyrosine phosphatase 1N (PTP1N) and PTP2N (IC50s = 2.5 and 1.8 nM, respectively). It is selective for PTP1N and ...

7. guidetopharmacology.org guidetopharmacology.org/GRAC/LigandDisplayForward?tab=clinical&ligandId=11968

ABBV-CLS-484 | Ligand page Initially the safety, PK and PD of ABBV-CLS-484 will be assessed in eligible patients with advanced solid tumours, and then its efficacy either as monotherapy ...

8. medchemexpress.com medchemexpress.com/osunprotafib.html?srsltid=AfmBOoqxtUi34nwj6_wI25cTae3eoR_06ToHYfUEH1Rh-LTvel9_Zz4W

Osunprotafib (ABBV-CLS-484) | PTPN1/PTPN2 Inhibitor Osunprotafib has 6-8-fold weaker activity on PTPN9 and no detectable activity on SHP-1 or SHP-2. Osunprotafib increases the sensitivity of human cancer cell ...