ABSK-021 for Cancer

Recruiting in Palo Alto (17 mi)

+8 other locations

Overseen by Siqing FU, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Abbisko Therapeutics Co, Ltd

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: Active CNS metastases, Cardiac disease, HIV, others

No Placebo Group

Approved in 2 Jurisdictions

Trial Summary

What is the purpose of this trial?

This trial tests a new pill called ABSK021 in people with serious tumors. It aims to find out if the pill is safe and can help shrink tumors.

Will I have to stop taking my current medications?

The trial requires that you stop any previous anti-cancer therapy, including chemotherapy, radiotherapy, endocrine therapy, or molecular targeted therapy, at least 4 weeks before starting the study treatment. Additionally, you cannot use strong inhibitors or inducers of CYP3A4 while participating in the trial.

What data supports the effectiveness of the drug ABSK021, Pimicotinib, for cancer?

Research on similar drugs, like buparlisib, shows that targeting the PI3K pathway can help treat certain cancers, such as breast cancer and lung cancer, by slowing tumor growth and overcoming treatment resistance. ^{1 2 3 4 5}

How is the drug ABSK-021 (Pimicotinib) different from other cancer treatments?

ABSK-021 (Pimicotinib) is unique because it targets specific mutations in the PIK3CA gene, which are common in various cancers. Unlike traditional treatments that affect both normal and mutated forms of the enzyme, this drug aims to reduce side effects by selectively inhibiting the mutant form, potentially improving safety and effectiveness. ^{6 7 8 9 10}

Research Team

Siqing FU, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for adults with advanced solid tumors, including Giant Cell Tumor of the tendon sheath or pigmented villonodular synovitis, who have tried other treatments without success or can't undergo surgery. Participants must be able to swallow pills, not have had recent cancer treatment or major surgery, and should not be pregnant or nursing.

Inclusion Criteria

ECOG (electrocorticogram) performance status 0~1

Life expectancy ≥ 3 months

Your organs and bone marrow are working properly.

Exclusion Criteria

Inability to take oral medication or significant nausea and vomiting, malabsorption, external biliary shunt, or significant bowel resection that would preclude adequate absorption of oral medication

Previous anti-cancer therapy, including chemotherapy, radiotherapy, endocrine therapy or molecular targeted therapy within ≤ 5-halflife or ≤ 4 weeks (whichever is shorter) prior to initiation of study treatment (chemotherapy with nitrosourea or mitomycin should be 6 weeks prior to initiation of study treatment)

Major surgery within 4 weeks of the first dose of study drug and all surgical wounds must be healed and free of infection or dehiscence

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Dose escalation of oral ABSK021 with a starting dose of 25mg once daily, guided by '3+3' escalation rules based on safety data until an MTD or RDE is identified.

28-day cycles

Multiple visits for dose administration and monitoring

Expansion

Expansion part of oral ABSK021 at recommended dose of expansion (RDE) for further evaluating safety and tolerability among selected tumor types.

28-day cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Treatment Details

Interventions

• ABSK021 (Unknown)

Trial Overview The study tests ABSK-021, an oral medication for advanced solid tumors. It's an early-phase trial to find out how safe it is and what dose works best. Researchers will also look at any signs that the drug might shrink the tumors.

Participant Groups

Group I: ABSK021 Experimental Treatment 1 Intervention

Dose escalation of oral ABSK021 with a starting dose of 25mg once daily will be guided by"3+3" escalation rules based on safety data until an MTD has been identified or a RDE. For each dose, patients will first receive a single dose ABSK021 tablet(s) by mouth at Day -3 and be followed by a 3-day off as a run-in period to access the safety and PK of single-dose. Then, patients will continuously receive ABSK021 once daily (QD) in repeated 28-day cycles.

ABSK021 is already approved in China for the following indications:

Approved in China as Pimicotinib for:

• Tenosynovial Giant Cell Tumor (TGCT)

Who Is Running the Clinical Trial?

Abbisko Therapeutics Co, Ltd

Lead Sponsor

Trials

26

Recruited

1,700+

Findings from Research

In a phase Ib study involving 146 patients with advanced solid tumors, the combination of pimasertib (a MEK1/2 inhibitor) and voxtalisib (a pan-PI3K and mTORC1/mTORC2 inhibitor) was found to have a maximum-tolerated dose of 90 mg and 70 mg respectively, with a recommended phase 2 dose of 60 mg for pimasertib.

Despite some initial responses, including one complete response and five partial responses, the treatment showed poor long-term tolerability, with 73% of patients requiring dose interruptions and 26% discontinuing due to treatment-emergent adverse events like diarrhea and fatigue.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase Ib dose-escalation and expansion study of the oral MEK inhibitor pimasertib and PI3K/MTOR inhibitor voxtalisib in patients with advanced solid tumours. Schram, AM., Gandhi, L., Mita, MM., et al.[2021]

In a phase Ib study involving patients with hormone therapy-refractory ER+ metastatic breast cancer, combining the PI3K inhibitor buparlisib with letrozole showed clinical benefits, particularly in patients with PIK3CA and MAP3K1 mutations.

Patients with both PIK3CA and MAP3K1 mutations had the highest likelihood of clinical benefit, suggesting that luminal A subtype tumors may be a key target population for this combination therapy, although the exact role of MAP3K1 mutations in response to treatment remains unclear.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PIK3CA and MAP3K1 alterations imply luminal A status and are associated with clinical benefit from pan-PI3K inhibitor buparlisib and letrozole in ER+ metastatic breast cancer. Nixon, MJ., Formisano, L., Mayer, IA., et al.[2023]

In a phase I trial involving 120 patients with solid tumors, apitolisib (GDC-0980) was found to be reasonably tolerated at a dose of 30 mg, with the recommended phase 2 dose (RP2D) established at 40 mg once daily, despite some severe side effects like hyperglycemia and pneumonitis.

The treatment showed promising preliminary antitumor activity, with 10 confirmed partial responses in various cancer types, and significant modulation of target pathways was observed, indicating its potential effectiveness as a cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Study of Apitolisib (GDC-0980), Dual Phosphatidylinositol-3-Kinase and Mammalian Target of Rapamycin Kinase Inhibitor, in Patients with Advanced Solid Tumors. Dolly, SO., Wagner, AJ., Bendell, JC., et al.[2022]

In a study of 1200 cancer patients, 11.8% had PIK3CA and/or PIK3R1 mutations, with a significant portion (78.4%) being activating mutations, indicating a potential role in various cancer types beyond just ER+/HER2- metastatic breast cancer.

The efficacy of first-line chemotherapy in ER+/HER2- metastatic breast cancer was similar for tumors with PIK3CA mutations compared to those without, while in triple-negative metastatic breast cancer, chemotherapy was more effective in tumors without PIK3CA mutations, suggesting the need for further evaluation of PI3K inhibitors in broader contexts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PIK3CA and PIK3R1 tumor mutational landscape in a pan-cancer patient cohort and its association with pathway activation and treatment efficacy. Tharin, Z., Richard, C., Derangère, V., et al.[2023]

In the BASALT-1 study, only 23.3% of squamous and 20.0% of nonsquamous NSCLC patients treated with the PI3K inhibitor buparlisib showed progression-free survival at 12 weeks, indicating limited efficacy as a monotherapy.

The study found that while PI3K pathway activation can be detected in circulating tumor DNA (ctDNA), it may not be the primary driver of tumor growth in NSCLC, suggesting that combining PI3K inhibitors with other treatments could be more effective.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of Buparlisib (BKM120) in Patients with PI3K Pathway-Activated Non-Small Cell Lung Cancer: Results from the Phase II BASALT-1 Study. Vansteenkiste, JF., Canon, JL., De Braud, F., et al.[2022]

In a study of 1,125 lung adenocarcinoma patients, 2% were found to have PIK3CA mutations, which often occurred alongside other mutations like EGFR and KRAS, indicating a complex genetic landscape in these tumors.

The presence of PIK3CA mutations in lung adenocarcinomas raises questions about their impact on the effectiveness of targeted therapies, suggesting that comprehensive genetic testing should be performed for better treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Coexistence of PIK3CA and other oncogene mutations in lung adenocarcinoma-rationale for comprehensive mutation profiling. Chaft, JE., Arcila, ME., Paik, PK., et al.[2023]

Advanced prostate cancers that are resistant to castration treatments are life-threatening and currently lack curative options, highlighting the urgent need for new therapies.

Recent studies indicate that the PI-3 kinase p110β is overexpressed in advanced prostate cancers and plays a crucial role in their development, leading to the development of specific inhibitors that are now being tested in clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PI-3 kinase p110β: a therapeutic target in advanced prostate cancers. Li, B., Sun, A., Jiang, W., et al.[2020]

Next-generation allosteric mutant and isoform-selective PIK3CA inhibitors show promise in targeting solid tumors with PIK3CA mutations, potentially offering improved efficacy and safety compared to traditional PI3K inhibitors that affect both mutant and wild-type forms.

Preclinical studies indicate that these selective inhibitors can effectively inhibit mutant PIK3CA without causing significant metabolic side effects, which are common with conventional PI3K inhibitors, although their effectiveness may vary for patients with multiple or rare mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The emerging role of PI3K inhibitors for solid tumour treatment and beyond. Belli, C., Repetto, M., Anand, S., et al.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

A phase Ib dose-escalation and expansion study of the oral MEK inhibitor pimasertib and PI3K/MTOR inhibitor voxtalisib in patients with advanced solid tumours. [2021]

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

PIK3CA and MAP3K1 alterations imply luminal A status and are associated with clinical benefit from pan-PI3K inhibitor buparlisib and letrozole in ER+ metastatic breast cancer. [2023]

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

Phase I Study of Apitolisib (GDC-0980), Dual Phosphatidylinositol-3-Kinase and Mammalian Target of Rapamycin Kinase Inhibitor, in Patients with Advanced Solid Tumors. [2022]

4. England pubmed.ncbi.nlm.nih.gov

PIK3CA and PIK3R1 tumor mutational landscape in a pan-cancer patient cohort and its association with pathway activation and treatment efficacy. [2023]

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

Safety and Efficacy of Buparlisib (BKM120) in Patients with PI3K Pathway-Activated Non-Small Cell Lung Cancer: Results from the Phase II BASALT-1 Study. [2022]

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

Phase II Study of Copanlisib in Patients With Tumors With PIK3CA Mutations: Results From the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocol Z1F. [2023]

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

Coexistence of PIK3CA and other oncogene mutations in lung adenocarcinoma-rationale for comprehensive mutation profiling. [2023]

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

STX-478, a Mutant-Selective, Allosteric PI3Kα Inhibitor Spares Metabolic Dysfunction and Improves Therapeutic Response in PI3Kα-Mutant Xenografts. [2023]

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

PI-3 kinase p110β: a therapeutic target in advanced prostate cancers. [2020]

10. England pubmed.ncbi.nlm.nih.gov

The emerging role of PI3K inhibitors for solid tumour treatment and beyond. [2023]