Targeted Therapy for Cancer

Recruiting at 1585 trial locations

Overseen By Marilyn Huang

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Warfarin, Protease inhibitors

Disqualifiers: Pregnancy, Uncontrolled illness, Cardiac issues, 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: 4

Duration: Up to 3 years

6452 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II MATCH screening and multi-sub-trial studies how well treatment that is directed by genetic testing works in patients with solid tumors, lymphomas, or multiple myelomas that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced) and does not respond to treatment (refractory). Patients must have progressed following at least one line of standard treatment or for which no agreed upon treatment approach exists. Genetic tests look at the unique genetic material (genes) of patients' tumor cells. Patients with genetic abnormalities (such as mutations, amplifications, or translocations) may benefit more from treatment which targets their tumor's particular genetic abnormality. Identifying these genetic abnormalities first may help doctors plan better treatment for patients with solid tumors, lymphomas, or multiple myeloma.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but it does mention that you must stop any systemic anti-cancer therapy before registration. Additionally, you cannot be on any investigational agents or certain medications that prolong the QT interval. It's best to discuss your specific medications with the trial team.

Is the combination of BRAF and MEK inhibitors generally safe for humans?

The combination of BRAF and MEK inhibitors, such as encorafenib plus binimetinib, has shown an acceptable safety profile in treating certain cancers, but it can cause serious side effects like skin issues, nerve problems, and kidney disorders. These treatments have improved survival rates in some cancer patients, but they also carry risks of severe adverse events that need careful monitoring. ^{1 2 3 4 5}

What makes the drug capivasertib unique in cancer treatment?

Capivasertib is a novel drug that targets the AKT pathway, which is often altered in cancers like breast cancer. It is unique because it can be used alone or in combination with other treatments, showing promise in shrinking tumors with specific genetic mutations. ^{6 7 8 9 10}

What data supports the effectiveness of the drug combination used in the Targeted Therapy for Cancer trial?

Research shows that binimetinib, a MEK inhibitor, has been effective in combination with other drugs for treating advanced solid tumors with specific genetic changes. Additionally, capivasertib, an AKT inhibitor, has shown promise in treating certain types of breast cancer when combined with other treatments. ^{1 6 7 11 12}

Research Team

Keith T Flaherty

Principal Investigator

ECOG-ACRIN Cancer Research Group

Eligibility Criteria

This trial is for patients with advanced solid tumors, lymphomas, or multiple myeloma that have worsened after standard treatment or lack a consensus treatment. Participants must be finished with previous treatments and recovered from their effects, not expect to conceive children, have an ECOG status of <=1 indicating they are relatively active, and meet specific health criteria including heart function and blood tests.

Inclusion Criteria

Patients of childbearing potential must have a negative serum pregnancy test within 2 weeks prior to registration; patients that are pregnant or breast feeding are excluded

Patients must not expect to conceive or father children by using accepted and effective method(s) of contraception or by abstaining from sexual intercourse prior to study entry, for the duration of study participation, and for 4 months after completion of study

It's been over 4 weeks since my last cancer treatment or major surgery, and any side effects are mild.

Exclusion Criteria

Patients living outside the US are excluded

I do not have any of the excluded medical conditions or treatments.

You have abnormal blood test results.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Patients are assigned to one of 38 treatment subprotocols based on molecularly-defined subgroup, with cycles repeating every 21 to 42 days depending on the subprotocol

Up to 3 years

Regular visits for treatment and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

3 years

Every 3 months for 2 years, then every 6 months for 1 year

Treatment Details

Interventions

• Afatinib
• Binimetinib
• Capivasertib
• Copanlisib
• Dabrafenib
• Dabrafenib Mesylate
• Dasatinib
• Defactinib
• Defactinib Hydrochloride
• Erdafitinib
• FGFR Inhibitor AZD4547
• Ipatasertib
• Larotrectinib
• Osimertinib
• PI3K-beta Inhibitor GSK2636771
• Sapanisertib
• Taselisib
• Ulixertinib
• Vismodegib

Trial Overview The MATCH trial is testing whether targeting therapy based on genetic abnormalities in the tumor cells can benefit patients whose cancer has progressed. It involves genetic testing to identify mutations or changes in the tumor's DNA and then matching patients with therapies specifically designed to target those genetic features.

Participant Groups

Group I: Subprotocol Z1M (LAG-3 expression >= 1%) Experimental Treatment 4 Interventions

Patients receive nivolumab IV over 30 minutes and relatlimab IV over 30 minutes on day 1.Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group II: Subprotocol Z1L (BRAF fusion, aberration or non-V600 mutation) Experimental Treatment 3 Interventions

Patients with a BRAF non-V600 mutation or BRAF fusion, or another BRAF aberration receive ulixertinib (BVD-523FB) PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group III: Subprotocol Z1K (AKT mutation) Experimental Treatment 3 Interventions

Patients receive ipatasertib PO QD. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group IV: Subprotocol Z1I (BRCA1 or BRCA2 gene mutation) Experimental Treatment 3 Interventions

Patients with BRCA1 or BRCA2 gene mutation receive adavosertib PO QD for 5 days for 2 weeks. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Group V: Subprotocol Z1H (PTEN mutation) Experimental Treatment 4 Interventions

Patients with PTEN mutation receive copanlisib IV over 1 hour on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group VI: Subprotocol Z1G (PTEN loss) Experimental Treatment 4 Interventions

Patients with PTEN loss receive copanlisib IV over 1 hour on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group VII: Subprotocol Z1F (PIK3CA mutation) Experimental Treatment 7 Interventions

Patients receive copanlisib IV over 1 hour on days 1, 8, and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo tumor biopsies at screening and end of treatment as well as CT or MRI at baseline and repeated every 2 cycles for the first 26 cycles then every 3 cycles thereafter until progressive disease or start of another MATCH treatment step.

Group VIII: Subprotocol Z1E (NTRK1, NTRK2 or NTRK3 gene fusion) Experimental Treatment 8 Interventions

Patients with NTRK1, NTRK2, or NTRK3 gene fusion receive larotrectinib (LOXO-101) PO BID on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo CT or MRI during screening and on study, as well as during follow-up as clinically necessary. Patients also undergo biopsies and blood sample collection on study.

Group IX: Subprotocol Z1D (Loss of MLH1 or MSH2 by IHC) Experimental Treatment 3 Interventions

Patients with mismatch repair deficiency (loss of MLH1 or MSH2 by IHC) receive nivolumab IV over 30 minutes on days 1 and 15 for 4 cycles and then on day 1 every 28 days. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group X: Subprotocol Z1C (CDK4 or CDK6 amplification and Rb protein) Experimental Treatment 3 Interventions

Patients with CDK4 or CDK6 amplification and tumor Rb protein receive palbociclib PO QD on days 1-21. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group XI: Subprotocol Z1B (CCND1, 2, or 3 amplification with Rb by IHC) Experimental Treatment 3 Interventions

Patients with CCND1, 2, or 3 amplification that have tumor Rb expression by IHC receive palbociclib PO QD for 21 days. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group XII: Subprotocol Z1A (NRAS mutation in codon 12, 13, or 61) Experimental Treatment 3 Interventions

Patients with NRAS mutation in codon 12, 13, or 61 receive binimetinib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group XIII: Subprotocol Y (Akt mutation) Experimental Treatment 3 Interventions

Patients with Akt mutation receive capivasertib PO BID on days 1-4, 8-11, 15-18, and 22-25. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group XIV: Subprotocol X (DDR2 S768R, I638F, or L239R mutation) Experimental Treatment 3 Interventions

Patients with DDR2 S768R, I638F, or L239R mutation receive dasatinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group XV: Subprotocol W (FGFR pathway aberrations) Experimental Treatment 3 Interventions

Patients with FGFR1-3 mutation or translocation receive FGFR Inhibitor AZD4547 PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group XVI: Subprotocol V (cKIT exon 9, 11, 13, or 14 mutation) Experimental Treatment 9 Interventions

Patients with cKIT exon 9, 11, 13, or 14 mutation receive sunitinib PO QD on days 1-28 of each cycle. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo CT or MRI during screening and on study, as well as during follow-up as clinically necessary. Patients also undergo ECHO or nuclear study throughout the trial as clinically necessary. Patients undergo biopsies and blood sample collection on study.

Group XVII: Subprotocol U (NF2 inactivating mutation) Experimental Treatment 4 Interventions

Patients with NF2 inactivating mutation receive defactinib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group XVIII: Subprotocol T (SMO or PTCH1 mutation) Experimental Treatment 9 Interventions

Patients with SMO or PTCH1 mutation receive vismodegib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO or nuclear study during screening, tumor biopsy on study and CT scan, MRI and blood sample collection throughout the study.

Group XIX: Subprotocol S2 (GNAQ or GNA11 mutation) Experimental Treatment 3 Interventions

Patients with GNAQ or GNA11 mutation receive trametinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group XX: Subprotocol S1 (NF1 mutation) Experimental Treatment 3 Interventions

Patients with NF1 mutation receive trametinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group XXI: Subprotocol R (BRAF fusion or BRAF non-V600 mutation) Experimental Treatment 3 Interventions

Patients with BRAF fusion or BRAF non-V600 mutation receive trametinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group XXII: Subprotocol Q (HER2 amplification) Experimental Treatment 4 Interventions

Patients with HER2 amplification receive trastuzumab emtansine intravenously (IV) over 30-90 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Group XXIII: Subprotocol P (PTEN loss) Experimental Treatment 3 Interventions

Patients with PTEN loss receive PI3K-beta inhibitor GSK2636771 PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group XXIV: Subprotocol N (PTEN mutation or deletion and PTEN expression) Experimental Treatment 3 Interventions

Patients with PTEN mutation or deletion and PTEN expression receive PI3K-beta inhibitor GSK2636771 PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group XXV: Subprotocol M (TSC1 or TSC2 mutation) Experimental Treatment 3 Interventions

Patients with TSC1 or TSC2 mutation receive sapanisertib PO daily on days 1-28. Cycles repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.

Group XXVI: Subprotocol L (mTOR mutation) Experimental Treatment 3 Interventions

Patients with mTOR mutation receive sapanisertib PO daily on days 1-28. Cycles repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.

Group XXVII: Subprotocol K2 (FGFR mutation or fusion) Experimental Treatment 7 Interventions

Patients with FGFR mutation or fusion receive erdafitinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection, CT or MRI, and tumor biopsy throughout the study.

Group XXVIII: Subprotocol K1 (FGFR amplification) Experimental Treatment 7 Interventions

Patients with FGFR amplification receive erdafitinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and MRI throughout study. Patients may also undergo blood sample collection and tumor biopsy throughout the trial.

Group XXIX: Subprotocol J (HER2 amplification >= 7 copy numbers) Experimental Treatment 9 Interventions

Patients receive pertuzumab IV over 30-60 minutes and trastuzumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo radiologic evaluation throughout the trial, ECHO at screening and end of treatment, and biopsy and collection of blood samples on trial and at end of treatment.

Group XXX: Subprotocol I (PIK3CA mutation) Experimental Treatment 3 Interventions

Patients with PIK3CA mutation without RAS mutation or PTEN loss receive taselisib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group XXXI: Subprotocol H (BRAF V600E/R/K/D mutation) Experimental Treatment 5 Interventions

Patients with BRAF V600E/R/K/D mutation receive dabrafenib PO BID and trametinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group XXXII: Subprotocol G (ROS1 translocation or inversion) Experimental Treatment 3 Interventions

Patients with ROS1 translocation or inversion receive crizotinib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group XXXIII: Subprotocol F (ALK translocation) Experimental Treatment 3 Interventions

Patients with ALK translocation receive crizotinib PO twice daily (BID) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group XXXIV: Subprotocol E (EGFR T790M or rare activating mutation) Experimental Treatment 8 Interventions

Patients with EGFR T790M or rare activating mutation receive osimertinib (AZD9291) PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo radiologic evaluation throughout the trial, ECHO or multigated acquisition scan (MUGA) during screening, and biopsy and collection of blood samples on trial and at end of treatment.

Group XXXV: Subprotocol C2 (MET exon 14 deletion/mutation) Experimental Treatment 6 Interventions

Patients with MET exon 14 deletion or other mutations that disrupt exon 14 receive crizotinib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo tumor biopsy on study and undergo radiologic evaluation and blood sample collection throughout the study.

Group XXXVI: Subprotocol C1 (MET amplification) Experimental Treatment 6 Interventions

Patients with MET amplification receive crizotinib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo radiologic evaluation and collection of blood samples throughout the study. Patients may undergo biopsy at screening, on study, and/or at end of treatment.

Group XXXVII: Subprotocol B (HER2 activating mutation) Experimental Treatment 4 Interventions

Patients with HER2 activating mutation receive afatinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group XXXVIII: Subprotocol A (EGFR activating mutation) Experimental Treatment 10 Interventions

Patients with EGFR activating mutation receive afatinib orally (PO) once daily (QD) on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo CT or MRI during screening and on study, as well as during follow-up as clinically necessary. Patients may also undergo ECHO or nuclear study throughout the trial as clinically necessary. Patients undergo biopsies and blood sample collection on study.

Afatinib is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Gilotrif for:

• Non-small cell lung cancer

Approved in European Union as Giotrif for:

• Non-small cell lung cancer

Approved in Canada as Gilotrif for:

• Non-small cell lung cancer

Approved in Japan as Giotrif for:

• Non-small cell lung cancer

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a phase Ib study involving 89 patients with advanced solid tumors, the combination of binimetinib (a MEK inhibitor) and buparlisib (a PI3K inhibitor) showed some efficacy, particularly in RAS/BRAF-mutant ovarian cancer, where 12% of patients achieved a partial response.

However, the treatment was associated with significant toxicities, leading to a lower than expected dose intensity, suggesting that alternative dosing strategies, like pulsatile dosing, may be necessary to improve safety and tolerability in future trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase Ib Study of Combination Therapy with MEK Inhibitor Binimetinib and Phosphatidylinositol 3-Kinase Inhibitor Buparlisib in Patients with Advanced Solid Tumors with RAS/RAF Alterations. Bardia, A., Gounder, M., Rodon, J., et al.[2023]

AZD5363, a pan-AKT inhibitor, shows promising efficacy in treating triple-negative metastatic breast cancer, especially in patients with specific genetic alterations, as indicated by a study involving 28 patient-derived xenografts (PDXs).

The study identified key biomarkers for sensitivity to AZD5363, such as mutations in PIK3CA/AKT1, and revealed mechanisms of resistance, including cyclin D1 overexpression, which could help tailor more effective treatments for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genetic Alterations in the PI3K/AKT Pathway and Baseline AKT Activity Define AKT Inhibitor Sensitivity in Breast Cancer Patient-derived Xenografts. Gris-Oliver, A., Palafox, M., Monserrat, L., et al.[2021]

Capivasertib, an oral AKT inhibitor, was well tolerated when combined with weekly paclitaxel in patients with advanced ER+/HER2- breast cancer, with a recommended dosing schedule of 400 mg twice daily for 4 days on and 3 days off.

However, the addition of capivasertib did not significantly improve progression-free survival compared to placebo, with median PFS of 10.9 months for capivasertib versus 8.4 months for placebo in the overall population, indicating it may not enhance treatment outcomes in this patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BEECH: a dose-finding run-in followed by a randomised phase II study assessing the efficacy of AKT inhibitor capivasertib (AZD5363) combined with paclitaxel in patients with estrogen receptor-positive advanced or metastatic breast cancer, and in a PIK3CA mutant sub-population. Turner, NC., Alarcón, E., Armstrong, AC., et al.[2023]

In a phase II study involving 98 patients with BRAFV600E-mutant metastatic non-small-cell lung cancer (NSCLC), the combination of encorafenib and binimetinib achieved a confirmed objective response rate of 75% in treatment-naïve patients and 46% in previously treated patients, indicating significant efficacy.

The treatment was generally well-tolerated, with common side effects including nausea (50%) and diarrhea (43%), but it also led to dose reductions in 24% of patients and one serious adverse event of intracranial hemorrhage, highlighting the importance of monitoring safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II, Open-Label Study of Encorafenib Plus Binimetinib in Patients With BRAFV600-Mutant Metastatic Non-Small-Cell Lung Cancer. Riely, GJ., Smit, EF., Ahn, MJ., et al.[2023]

Neratinib combined with paclitaxel showed a high overall response rate of 73% in patients with HER2-positive breast cancer, indicating its efficacy as a treatment option.

The combination therapy had manageable side effects, with common adverse events including diarrhea and peripheral sensory neuropathy, but no dose-limiting toxicities were observed during the study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination neratinib (HKI-272) and paclitaxel therapy in patients with HER2-positive metastatic breast cancer. Chow, LW., Xu, B., Gupta, S., et al.[2023]

The combination of encorafenib and binimetinib was found to be safe and showed promising activity in patients with BRAF V600E-mutant solid tumors, with a recommended phase 2 dose established for further studies.

In phase II, the treatment resulted in confirmed responses in 67% of BRAFi-naïve melanoma patients, indicating significant efficacy, while the most common serious side effect was increased alanine aminotransferase levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase Ib/II Study of the BRAF Inhibitor Encorafenib Plus the MEK Inhibitor Binimetinib in Patients with BRAFV600E/K -mutant Solid Tumors. Sullivan, RJ., Weber, J., Patel, S., et al.[2021]

A review of 11,721 serious adverse event reports from patients treated with BRAF and MEK inhibitors revealed that different combinations have unique safety profiles, with V+C showing a high incidence of skin toxicities like Stevens-Johnson syndrome.

The combination E+B was notably associated with an increased risk of peripheral neuropathies and renal disorders, as well as a significant rise in reports of Guillain-Barré syndrome, indicating that while these treatments improve survival in melanoma, they also carry serious risks that need careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of BRAF+MEK Inhibitor Combinations: Severe Adverse Event Evaluation. Meirson, T., Asher, N., Bomze, D., et al.[2020]

In a study of 185 patients with advanced melanoma, the combination therapy of dabrafenib and trametinib (CombiDT) showed a significantly lower incidence of serious skin issues, such as cutaneous squamous cell carcinoma, compared to single-agent BRAF inhibitors like dabrafenib and vemurafenib.

While CombiDT therapy resulted in a higher occurrence of folliculitis, it eliminated the risk of other severe skin conditions associated with BRAF inhibitors, highlighting its potential for safer treatment in melanoma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cutaneous Toxic Effects of BRAF Inhibitors Alone and in Combination With MEK Inhibitors for Metastatic Melanoma. Carlos, G., Anforth, R., Clements, A., et al.[2022]

A study analyzing 1568 reported cases of ocular adverse effects (OAEs) from BRAF and MEK inhibitors found that BRAF monotherapy is significantly linked to various eye issues, including iris and ciliary body abnormalities and anterior uveitis, indicating a need for careful monitoring of these side effects.

MEK inhibitor monotherapy was associated with retinal and choroid abnormalities, and the combination therapy of BRAF and MEK inhibitors showed potential for increased ocular toxicity, suggesting that personalized management strategies are necessary for patients undergoing combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ocular Safety Profile of BRAF and MEK Inhibitors: Data from the World Health Organization Pharmacovigilance Database. Mettler, C., Monnet, D., Kramkimel, N., et al.[2021]

Capivasertib is a novel AKT inhibitor that has shown promising efficacy in treating breast cancer, particularly in tumors with specific genetic alterations, and is more effective when combined with other treatments like paclitaxel and fulvestrant.

The recommended dosing schedule for capivasertib is 480 mg twice daily for four days followed by three days off, with manageable side effects including hyperglycemia and diarrhea, indicating a favorable safety profile for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

"The emerging role of capivasertib in breast cancer". Andrikopoulou, A., Chatzinikolaou, S., Panourgias, E., et al.[2022]

In a phase II trial involving 150 patients with metastatic castration-resistant prostate cancer (mCRPC), the addition of capivasertib to standard chemotherapy did not significantly prolong composite progression-free survival (cPFS) compared to placebo, with median cPFS of 7.03 months for capivasertib versus 6.70 months for placebo.

However, capivasertib was associated with a significant improvement in overall survival (OS), with a median OS of 31.15 months for the capivasertib group compared to 20.27 months for the placebo group, suggesting potential benefits that warrant further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pan-AKT Inhibitor Capivasertib With Docetaxel and Prednisolone in Metastatic Castration-Resistant Prostate Cancer: A Randomized, Placebo-Controlled Phase II Trial (ProCAID). Crabb, SJ., Griffiths, G., Marwood, E., et al.[2022]

References

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

Phase Ib Study of Combination Therapy with MEK Inhibitor Binimetinib and Phosphatidylinositol 3-Kinase Inhibitor Buparlisib in Patients with Advanced Solid Tumors with RAS/RAF Alterations. [2023]

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

Genetic Alterations in the PI3K/AKT Pathway and Baseline AKT Activity Define AKT Inhibitor Sensitivity in Breast Cancer Patient-derived Xenografts. [2021]

3. England pubmed.ncbi.nlm.nih.gov

BEECH: a dose-finding run-in followed by a randomised phase II study assessing the efficacy of AKT inhibitor capivasertib (AZD5363) combined with paclitaxel in patients with estrogen receptor-positive advanced or metastatic breast cancer, and in a PIK3CA mutant sub-population. [2023]

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

Phase II, Open-Label Study of Encorafenib Plus Binimetinib in Patients With BRAFV600-Mutant Metastatic Non-Small-Cell Lung Cancer. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Combination neratinib (HKI-272) and paclitaxel therapy in patients with HER2-positive metastatic breast cancer. [2023]

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

A Phase Ib/II Study of the BRAF Inhibitor Encorafenib Plus the MEK Inhibitor Binimetinib in Patients with BRAFV600E/K -mutant Solid Tumors. [2021]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Safety of BRAF+MEK Inhibitor Combinations: Severe Adverse Event Evaluation. [2020]

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

Cutaneous Toxic Effects of BRAF Inhibitors Alone and in Combination With MEK Inhibitors for Metastatic Melanoma. [2022]

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

Ocular Safety Profile of BRAF and MEK Inhibitors: Data from the World Health Organization Pharmacovigilance Database. [2021]

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

Capivasertib Active against AKT1-Mutated Cancers. [2019]

11. Netherlands pubmed.ncbi.nlm.nih.gov

"The emerging role of capivasertib in breast cancer". [2022]

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

Pan-AKT Inhibitor Capivasertib With Docetaxel and Prednisolone in Metastatic Castration-Resistant Prostate Cancer: A Randomized, Placebo-Controlled Phase II Trial (ProCAID). [2022]