Aliqopa (copanlisib)

P2, N=1, Terminated, Columbia University | Active, not recruiting --> Terminated; Enrollment challenges

Some PI3K inhibitors such as idelalisib, copanlisib, duvelisib, alpelisib, and umbralisib have received FDA-approval, and are effective in the treatment of breast cancer and haematologic malignancies. The resistance mechanisms provide barriers to the sustained efficacy of PI3K-targeted treatments. This study reviews recent advancements in PI3K inhibitors, covering their clinical status, mechanism of action, resistance mechanisms, and strategies to overcome resistance.

P1/2, N=8, Active, not recruiting, City of Hope Medical Center | Trial completion date: Nov 2024 --> Mar 2025 | Trial primary completion date: Nov 2024 --> Mar 2025

Additive and/or synergistic effects were observed with alpelisib or inavolisib or copanlisib in combination with a RAS/MEK/ERK pathway inhibitor, either selumetinib (MEK), ravoxertinib (ERK 1/2), or tovorafenib (DAY101, RAF). Combinations of each of these three PI3K inhibitors with the KRAS mutation specific inhibitors MTRX1133 (KRAS G12D) or sotorasib (KRAS G12C) had selective activity in cell lines harboring the corresponding target. Lastly, combination effects were observed from vertical inhibition of the PI3K/AKT/mTOR pathway with a PI3K inhibitor in combination with either the mTORC1/2 inhibitor sapanisertib or an AKT inhibitor, ipatasertib or afuresertib.

PTEN presence, BCL2 mutations, and low or undetectable baseline IL-2 levels were associated with improved patient survival following treatment with C + R, supporting a potential role for these biomarkers in guiding treatment selection for patients with indolent non-Hodgkin lymphoma.

Finally, in both HA cell lines AKT kinase was hyperphosphorylated and the cells showed increased sensitivity to copanlisib, a pan-PI3K inhibitor...Increased dependence on BCL-XL and PI3K-AKT signaling for survival. In translation, inhibition of glycolysis, BCL-XL, or PI3K-AKT cascade may result in targeted elimination of HA lymphoma cells.

Our results do not support the antitumor activity of single-agent copanlisib in tumors with PTEN loss regardless of mutation or deletion status or PTEN deleterious mutations with PTEN expression.

P1/2, N=102, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Dec 2025

However, the combination of copanlisib and afatinib completely blocked phosphorylation of the ErbB family (including HER3) and Akt, while also increasing apoptosis. In conclusion, these results suggested that co‑targeting the ErbB family kinases and PI3K using a combination treatment of afatinib and copanlisib may have clinical potential for patients with HPV‑negative HNSCC.

Pirtobrutinib, copanlisib, sirolimus, vorinostat, and tocilizumab were associated with high infectious complications (>30%) that warrant emphasis in the clinical guidelines. Thus, clinicians should vigilantly monitor patients undergoing immune and targeted therapies for infectious complications and use antimicrobial prophylaxes when indicated.

P1, N=27, Active, not recruiting, City of Hope Medical Center | Trial completion date: Dec 2024 --> Jul 2025 | Trial primary completion date: Dec 2024 --> Jul 2025

P3, N=458, Completed, Bayer | Active, not recruiting --> Completed

Initial treatments, including carboplatin, etoposide, and taxane-based chemotherapy, were ineffective. After 76 cycles, she continues to tolerate therapy well with minimal adverse events. This case highlights the potential of targeted therapies such as copanlisib for treating METAM, providing a promising therapeutic option for patients with PIK3CA mutations.

Human papilloma virus-negative head and neck squamous cell carcinoma (HNSCC) frequently harbors 11q13 amplifications. Copanlisib and afatinib were identified as promising candidates for combination therapy of 11q13-amplified HNSCC tumors. We demonstrated a predominant role for Ano1 in treatment resistance in Cyclin D1highAno1high HNSCC tumors and identified novel potential treatment combinations for this high-risk patient group.

P1/2, N=29, Not yet recruiting, VA Office of Research and Development | Trial completion date: Dec 2028 --> Jun 2029 | Trial primary completion date: Jun 2028 --> Dec 2028

P2, N=37, Terminated, Fondazione Italiana Linfomi - ETS | Active, not recruiting --> Terminated; low enrollment rate

P2, N=37, Terminated, Fondazione Italiana Linfomi - ETS | Active, not recruiting --> Terminated; low enrollment rate

P1/2, N=48, Active, not recruiting, Dana-Farber Cancer Institute | Trial primary completion date: Sep 2024 --> Jun 2025

P1/2, N=106, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2024 --> Jun 2025 | Trial primary completion date: Dec 2024 --> Jun 2025

P1, N=64, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jul 2024 --> Jul 2026 | Trial primary completion date: Jul 2024 --> Jul 2026

P1; Phase classification: P1/2 --> P1 | Trial completion date: Mar 2025 --> Jul 2025

P1/2, N=0, Withdrawn, Memorial Sloan Kettering Cancer Center | N=37 --> 0 | Active, not recruiting --> Withdrawn

P=N/A, N=6, Completed, Bayer | Active, not recruiting --> Completed | N=50 --> 6

P1/2, N=37, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Recruiting --> Active, not recruiting

P1, N=6, Terminated, University of Michigan Rogel Cancer Center | N=35 --> 6 | Trial completion date: Jun 2026 --> Nov 2023 | Active, not recruiting --> Terminated | Trial primary completion date: Jun 2025 --> Nov 2023; Loss of study funding

Then, an in silico docking with these lichen-derived metabolites against the PI3Kα receptor predicted these compounds has a binding affinity close to a standard PI3Kα inhibitor copanlisib. The study concludes that the extract restricts lung cancer possibly through the PI3Kα/FOXO1 axis and thus Parmelinella wallichiana represents a potential resource for anti-lung cancer drug development in future.

P2, N=37, Active, not recruiting, Fondazione Italiana Linfomi - ETS | Trial completion date: Aug 2024 --> Dec 2024 | Trial primary completion date: Aug 2024 --> Dec 2024

P1, N=27, Active, not recruiting, City of Hope Medical Center | Trial completion date: Jul 2024 --> Dec 2024 | Trial primary completion date: Jul 2024 --> Dec 2024

Alpelisib (inhibiting PI3Kα), copanlisib (inhibiting PI3Kα andPI3Kδ), duvelisib (inhibiting PI3Kδ and PI3Kγ), and idelalisib (inhibitingPI3Kδ) were developed to target the PI3K pathway...The safety profiles of the five PI3K inhibitorsvary concerning adverse events. These findings could guide drug selection andinform future prospective research.

When camidanlumab tesirine-containing combinations were evaluated in four T-cell lymphoma models, the most active partners were everolimus, copanlisib, venetoclax, vorinostat, and pralatrexate, followed by bortezomib, romidepsin, bendamustine, and 5-azacytidine. The strong camidanlumab tesirine single-agent anti-lymphoma activity and the in vitro synergisms with targeted agents identify potential combination partners for future clinical studies.

P1, N=8, Terminated, National Cancer Institute (NCI) | Completed --> Terminated; The study was terminated early because copanlisib was removed from the market by the Food and Drug Administration (FDA) and the manufacturer.

Finally, the combination of the HSP110 inhibitor with the PI3K inhibitor copanlisib decreases SYK/BTK and AKT phosphorylation synergistically, leading to suppression of tumor growth in cell line xenografts and strong reduction in patient-derived xenografts. In conclusion, by regulating the BCR/TLR signaling pathway, HSP110 inhibitors are potential drug candidates for ABC-DLBCL patients.

For instance, RTK inhibitors such as imatinib and afatinib selectively target these receptors, hindering ligand binding and reducing signaling initiation...Other inhibitors, like lonafarnib targeting Farnesyltransferase and GGTI 2418 targeting geranylgeranyl Transferase, disrupt post-translational modifications of proteins...Targeting downstream components with RAF inhibitors such as vemurafenib, dabrafenib, and sorafenib, along with MEK inhibitors like trametinib and binimetinib, has shown promising outcomes in treating cancers with BRAF-V600E mutations, including myeloma, colorectal, and thyroid cancers. Furthermore, inhibitors of PI3K (e.g., apitolisib, copanlisib), AKT (e.g., ipatasertib, perifosine), and mTOR (e.g., sirolimus, temsirolimus) exhibit promising efficacy against various cancers such as Invasive Breast Cancer, Lymphoma, Neoplasms, and hematological malignancies. This review offers an overview of small molecule inhibitors targeting specific proteins within the RAS upstream and downstream signaling pathways in cancer.

P1, N=31, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2023 --> Dec 2026 | Trial primary completion date: Dec 2023 --> Dec 2026

P2, N=7, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Aug 2024 --> Oct 2026 | Trial primary completion date: Aug 2024 --> Oct 2026

P1/2, N=8, Active, not recruiting, City of Hope Medical Center | Suspended --> Active, not recruiting | N=23 --> 8

The Pan-PI3K-inhibitor wortmannin and its clinical derivative, PX-866, were identified to act as senolytics...Other Pan-PI3K inhibitors, such as the FDA-approved drug BAY80-6946 (Copanlisib, Aliqopa®), also efficiently and specifically eliminated senescent cells. Interestingly, only the simultaneous inhibition of both PI3K class I alpha (with BYL-719 (Alpelisib, Piqray®)) and delta (with CAL-101 (Idelalisib, Zydelig®)) isoforms was sufficient to induce senolysis, whereas single application of these inhibitors had no effect...This led to a timely induction of apoptosis in senescent tumor cells. Taken together, the senolytic properties of PI3K-inhibitors reveal a novel dimension of these promising compounds, which holds particular potential when employed alongside DNA damaging agents in combination tumor therapies.

P3, N=458, Active, not recruiting, Bayer | Trial completion date: May 2024 --> Aug 2024

These data support further clinical development for the combination of copanlisib and eribulin. These data led to a phase I/II trial of copanlisib and eribulin in patients with metastatic TNBC.

P2, N=35, Active, not recruiting, National Cancer Institute (NCI)

However, combinations of copanlisib/afatinib and copanlisib/elimusertib were significantly more effective in controlling NETc tumor growth. These findings define the genetic landscape of NETc and suggest that a large subset of these highly lethal malignancies might benefit from existing targeted therapies.

P2, N=35, Active, not recruiting, National Cancer Institute (NCI)