ACP-319,Cancer Cure in Trials?

ACP-319 Report-Drug and Patient use and information

Age group

Adults: aged 18 and over. (ClinicalTrials.gov,2022)

Drug action

The PI3K (phosphatidylinositol 3-kinase)-pathway is a cellular signalling pathway, that regulates cell proliferation and growth but overstimulating growth of these cells can cause cancer/tumours, such as Chronic Lymphocytic Leukaemia (CLL). (Uko, Guner, Matesic and Bowen, 2020).

ACP-319 is a PI3K Inhibitor, meaning it inhibits the progression of this signalling pathway, preventing the tumour growth and so can provide as a potentially good anticancertreatment. (Sabbah, Hajjo, Bardaweel and Zhong,2021) (Isoyama, Mori,Sugiyama, Kojima, Tada, Shitara, Hinohara,Dan and Nishikawa,2021/2022).

Indications and dose

• ACP-319, PI3K inhibitor, helps treat many cancers including (CLL) and other B-cell malignancies. Therefore, an anticancer treatment. (Adis Insight, 2021).

• Used for relapsed patients, including CLL or those refractory to 1 or more CLL-related treatment. (ClinicalTrials.gov,2022)

Administration

Oral medication. (Barr, Smith, Roschewski, O’Brien,Sharman, Melear, Patel, Calvo, Yang, and Spurgeon, 2022)

Dosing

(25mg-100mg) 25mg, 50mg or 100mg, taken twice daily. (Barr, Smith, Roschewski, O’Brien,Sharman, Melear, Patel, Calvo, Yang, and Spurgeon, 2022)

Contraindications

Those with the following should not use the drug-treatment:

• Healthy individuals without cancer e.g. CLL or related diseases/condition/cancer.

• Adults not aged 18 or over

• Having medical conditions or life-threatening illnesses, that may affect the absorption/metabolism of ACP-319 Therefore for safety reasons. (ClinicalTrials.gov,2022)

• Have had a previous tumour, apart from sufficiently treated basal cell or squamous cell skin cancer, in situ cervical cancer or a different cancer not present for more than two years or provides less-than two years chance of survival.

• Major Cardiovascular disease.

• Malabsorption syndrome or diseases affecting the stomach, intestines, or bowel movements.

• Undergoing of immunotherapy within four weeks from taking the first dose.

• History of previous allogenic bone marrow progenitor cell or solid organ transplantation

• Continuing immunosuppressive therapy, including enteric or corticosteroids for CLL treatment.

• Affection of the nervous system by/from CLL.

• Apart from Alopecia, toxicity at a level or two or more.

• HIV (Human Immunodeficiency Virus) history, current infection with HCV or HBV: (Hepatitis C or B virus) or other active uncontrolled systemic infection.

• Uncontrolled autoimmune haemolytic anaemia or idiopathic thrombocytopenia purpura.

• Those with: Absolute neutrophil count less than 0.75X109/L

▪ Platelet count less than: 50x109/L unless related with disease in bone marrow

• Creatinine is more than: 1.5x institutional upper limit of normal (ULN)

• Total bilirubin is more than 1.5xULN (unless is because of Gilbert’s disease)

• Aspartate aminotransferase (AST) or alanine transferase (ALT) levels are more than 2.5x ULN, unless disease-associated.

• Major ECG abnormalities, from screening which includes left bundle branch block, second-degree AV block type II, third-degree block, Grade 2 or higher bradycardia and QTc: more-than 48msec.

(ClinicalTrials.gov,2022)

Cautions

• Adults with CLL diagnosis, relapsed or been ‘refractory to’ more than 1 CLL treatment-method.

• Participants with 17p-deletion if they have relapsed or been refractory to at least 1 CLL treatment before.

(ClinicalTrials.gov,2022)

Side effects and further information

Side effects:

• Diarrhoea- from inadequate drug response to antimotility agents, (Gilead,2014), (Mishra, Patel, Alanazi, Kilroy and Garrett ,2021)

• Upper respiratory tract infection,

• Nausea,

  Dizziness- from red-blood-cell reduction in CLL,

• Headache,

• Cough,

• Abdominal pain,

• Fatigue,

• Rash,

• Hypotension,

• Decreased appetite,

• Thrombocytopenia,

• Contusion,

• Edema peripheral

• progressive disease.

  (Barr, Smith, Roschewski, O’Brien, Sharman, Melear, Patel, Calvo, Yang and Spurgeon, 2022) (ClinicalTrials.gov,2022) ∗2 .

Serious Adverse-reactions (but more uncommon):

• Anaemia

• Febrile neutropenia

• Atrial flutter,

• Pericardial effusion,

• Abdominal pain,

• Intestinal ischaemia,

• lower gastrointestinal hemorrhage,

• pancreatitis acute,

• asthenia, pyrexia,

• immune-mediated hepatitis- which can occur due to elevated liver function from tests, requiring corticosteroid treatment,

  (Barr, Smith, Roschewski, O’Brien,Sharman, Melear, Patel, Calvo, Yang and Spurgeon, 2022) (Mishra, Patel, Alanazi, Kilroy and Garrett,2021)

• cellulitis,

• influenza,

• pulmonary nocardiosis,

• femoral neck fracture,

• diabetic ketoacidosis,

• malignant melanoma,

• cognitive disorders,

• hemiparesis, normal pressure hydrocephalus,

• embolism and hypotension,

• increase in: alanine aminotransferase,

• aspartate aminotransferase,

• blood lactic acid and transaminase,

  (ClinicalTrials.gov,2022) ∗2

• myelodysplastic syndrome,

• maculopapular rash

• pneumonitis.

(Barr, Smith, Roschewski, O’Brien,Sharman, Melear, Patel, Calvo, Yang and Spurgeon, 2022).

Conception and contraception

Recommended contraception during treatment and for thirty days after last dose of treatment, in sexually active women and women with childbearing desire. (ClinicalTrials.gov,2022)

Pregnancy

Should be avoided as can cause ‘foetal harm’. (accessdata.fda.gov,2022) (Mishra, Patel, Alanazi, Kilroy and Garrett,2021).

Breastfeeding

Should be avoided as PI3K have high and varying toxicity and effect dividing-cells in body. (Fenner, 2020) (Mishra, Patel, Alanazi, Kilroy and Garrett,2021). Also, because immunotherapy/targeted-therapy can be passed into the baby, through feeds. (MACMILLAN CANCER SUPPORT, 2019).

Pre-treatment screening

• Adults, aged 18-and-over, with confirmed CLL, which has relapsed or not worked against one or more treatment-method, including those with the 17p deletion.

Those with:

• An Eastern Cooperative Oncology Group (ECOG) performance level of two or more.

• Major cardiovascular or life-threatening conditions which are potential sideeffects/adverse-reactions.

(ClinicalTrials.gov,2022)

Monitoring requirements

Conditions to look out for when patients are undergoing therapy are: Thrombocytopenia, adverse reactions, erythema, neutropenia

(Barr, Smith, Roschewski, O’Brien,Sharman, Melear, Patel, Calvo, Yang and Spurgeon, 2022) and Pneumonitis, which is monitored looking at:

• Pulmonary symptoms

• ALT and AST-levels, every two weeks for three months, then four weeks and then 1 week, each for a consecutive three months

• Liver toxicity if levels rise three times the ULN.

(Gilead,2014) (Mishra, Patel, Alanazi, Kilroy, and Garrett,2021)

Prescribing and dispensing information

ACP-319 can be taken with:

• Corticosteroids and when/if experience side effects of reversible-hepatotoxicity (may be immune-related) in liver enzymes, from ACP-319/PI3K-inhibitor-drugs.

(Barr, Smith, Roschewski, O’Brien,Sharman, Melear, Patel, Calvo, Yang and Spurgeon, 2022)

• Analgesics, which help inhibit the PI3K-pathway.

(Mozolewski, Moskot, Jakóbkiewicz-Banecka, Węgrzyn, Bocheńska,Banecki and Gabig-Cimińska,2017), (Gilead,2014)

• ACP-196/Acalabrutinib-(BTK-inhibitor)

(Niemann, Mora-Jensen, Dadashian, Krantz, Covey, Chen, Chiorazzi, Izumi, Ulrich,Lannutti,Wiestner and Herman,2017)

2. Pembrolizumab and ACP-319 combination recommendation.

Taking Pembrolizumab and ACP-319 in combination can be used, as both aim to destroy cancer and tumour-cells to prevent its development, specifically for Beta(B)-cell cancers, including CLL and others. (Acerta Pharma BV,2022), (National Institute for Health and Care Excellence, no date) Individuals with related-diseases should be provided with the drug, unless they meet the exclusion criteria, as discussed below.

ACP-319 is a PI3K-inhibtor, inhibiting signalling pathways to control cell growth and prevent tumour formation and Pembrolizumab, a monoclonal-antibody bound to the programmed death-1 (PD-1) receptor that undergoes Immune-checkpoint-blockades (ICB). Moreover, PI3K-inhbitors and PD-1 receptors work well in combination as they improve antitumor effects, proved in a study with cancer patients, taking this PI3K-inhibitor and PD-1 blockade drug-combination. (Isoyama, Mori, Sugiyama, Kojima, Tada, Shitara, Hinohara, Dan and Nishikawa, 2021/2022).

The combination works as higher doses of PI3K-inhibitor administration damages the activation of CD8 + T-cells and Tregs (T-regulatory cells).(Kondĕlková, Vokurková, Krejsek, Borská, Fiala and Ctirad,2010). The doses and timing of this drug-combination are important as they decrease ‘intratumoral’ Tregs. This results in tumour antigen-specific CD8 + T-cell production. With the administration of the PI3K-inhibitor and optimal dosing for specific deletion of T-regulatory-cells, signals related to PI3K are inhibited in these T-cells and activated CD8 + T-cells. Moreover, causing a large generation of tumour antigen-specific memory CD8 + T-cells, for strong antitumor immunity. (Isoyama, Mori, Sugiyama, Kojima, Tada, Shitara, Hinohara, Dan and Nishikawa, 2021/2022). Therefore, potentially recommending a higher dose of the combination-drug.

Despite the great interaction between the drug-types, there are many side-effects and possible adverse-reactions that can occur. Overlapping side-effects of both drugs include: diarrhoea, respiratory related issues, nausea, dizziness, headache, cough, skin reactions/rash and decrease in appetite which can be present in many drugs. However, these adverse-reactions are more rare and uncommon to develop. (ClinicalTrials.gov,2022). Additionally, side-effects in other cancer-treatments such as Chemotherapy can be more painful and worse but can still help to treat the cancer. Therefore, chance can be provided with this drug-combination too and a point for further research.

Pembrolizumab can cause infusion-related hypersensitivity, as due to its parenteral administration. (National Institute for Health and Care Excellence, no date) ACP-319, is given orally. (Barr, Smith Roschewski, O’Brien,Sharman, Melear, Patel, Calvo, Yang and Spurgeon, 2022). However, if this combination was administered through infusion, infusion-related allergy sufferers, should not be treated with it, to avoid hypersensitivity and possible life-threatening reactions.

Pregnant and breastfeeding women should also avoid this combination as it can negatively affect the baby, as advised with the drugs individually. (accessdata.fda.gov,2022) (Fenner, 2020) (National Institute for Health and Care Excellence, no date) (Mishra, Patel, Alanazi, Kilroy and Garrett,2021).

Also those with: thrombocytopenia, anaemia, (severe) abdominal or gastrointestinal related disorders, respiratory or hepatic disorders, asthenia, major nerve or joint disorders, (type 1) diabetic ketoacidosis, increased risk of infection or influenza, have certain skin conditions e.g Myelodysplastic syndrome, are not aged 18-and-over or have any other life-threatening illnesses should not be recommend this drug-combination. This is because, despite the adverse-reactions being uncommon, there is still possible and miniscule chance of development in higher-risk patients. Similarly, those with cardiovascular-related disorders, HIV, Hepatitis B and C, Absolute-neutrophil-count less than 0.75X109/L and Platelet count less than: 50x109/L, unless related to disease in in bone marrow should not be recommended this drug-combination.(ClinicalTrials.gov,2022), (National Institute for Health and Care Excellence, no date).

Likewise, Pembrolizumab alone can cause genital-abnormalities and renal-impairment so should not be recommended to those patients. (National Institute for Health and Care Excellence, no date) Similarly, to those with hypotension, which is an ACP-319 side-effect. (National Institute for Health and Care Excellence, no date), (ClinicalTrials.gov,2022).

These conditions should be checked for and recorded within a patient history to know whether the patient is at further-risk or suitable for/from drug administration.

Those that suffer from conditions under monitoring: Thrombocytopenia, erythema, neutropenia, pulmonary symptoms from Pneumonitis, ALT and AST-levels and liver toxicity should not be recommended this drug-combination. (Gilead,2014) (Mishra, Patel, Alanazi, Kilroy and Garrett ,2021), (National Institute for Health and Care Excellence, no date)(Barr, Smith, Roschewski, O’Brien, Sharman, Melear, Patel, Calvo, Yang and Spurgeon, 2022).

Other patients who should not be given the combined-drug are from the individual drug reactions as: taking Pembrolizumab increases risk of severe-graft-versus host-reaction in patients who have had previous hematopoietic-stem-cell transplant. (National Institute for Health and Care Excellence, no date) Similarly, with ACP-319 those with a previous tumour from a cancer not occurred for more-than 2 years. (ClinicalTrials.gov,2022).

However, with ACP-319 those relapsed or ‘refractory to’ more than 1 CLL treatment-method patients may be given ACP-319 treatment. (ClinicalTrials.gov,2022).

Overall, it could be recommended for the combination of ACP-319 and Pembrolizumab to be given in combination as from their successful and targeted working mechanisms in conjunction, providing a potential treatment source for cancer therapy. (Isoyama, Mori, Sugiyama, Kojima, Tada, Shitara, Hinohara, Dan and Nishikawa, 2021/2022). (ClinicalTrials.gov,2022). Also, despite the presence of adverse-reactions, these are usually more rare but those with higher-risk or already suffering from these conditions, should not be prescribed the drug. Whereas, could be a potential and supportive anti-cancer treatment for others. (Isoyama, Mori, Sugiyama, Kojima, Tada, Shitara, Hinohara, Dan and Nishikawa, 2021/2022).

(Younes, Brody,Carpio, Lopez-Guillermo,Ben-Yehuda,Ferhanoglu, Nagler, Ozcan, Avivi, Bosch, Barrigón, , Hellmann, Kuss,, Ma,Demirkan, Yağci, Horowitz, Marlton, Cordoba,Wrobel, Buglio, Streit, Hodkinson, Schaffer, Alvarez, Ceulemans,Balasubramanian, Jong, Wang, Fourneau and Jurczak,2019)

3. Further suggestions

Further suggestions, apart from checking for the diseases related to the drug sideeffects/adverse-reactions, required from patients would be to look at patient genetics and history, to check for suitability of the drug, for CLL.

Patients can be sent for genetic-testing, to check for CLL specifically and B-cell malignancies as through the chromosomal mutations in mainly chromosomes 13, with deletion of the 13q14 region and 17, deletion of 17p region and sometimes chromosome-11, where the 11q23 region is deleted. Additionally, those with a family history of CLL are at higher risk of development but does not mean will definitely develop CLL. (Cancer research UK,2021).

Regarding deletion of region: 13q14.2, there is a sequence for 2 micro-RNA sequences: miR15A and miR16A which in normal condition inhibit expression of an anti-apoptotic protein: BCL2, causing apoptosis. Whereas in CLL, there are no micro-RNA’s to block BCL2, which causes inhibition of apoptosis, increasing B-cell lifespan. The more proliferation and B-cell number, causes higher chance of CLL, which can be seen completing a patient-bloodfilm. In the 17q deletion, the TP53 gene encodes for the p53 protein, which when mutated causes DNA damage repair and apoptosis to not be activated, therefore increasing B-cell number and chance of CLL.

Furthermore, when taking a patient history, symptoms of CLL should be checked for, despite patients normally being asymptomatic: enlarged lymph-nodes, axillary-regions and spleen as the B-cells, made in the bone-marrow, travel and wait for immune-system disruption and to fight against it. This B-cell build-up causes the swelling of these areas. Other symptoms are night sweats, due to change in hormones from cancerous B-cells, weight-loss, anaemia, pallor and dyspnea, thrombocytopenia with bruising or purpura and/or hypogammaglobulinaemia and cellular immune dysfunction, which both increase the risk of bacterial or viral infections.

Bibliography

• Accessdata.fda.gov (2022) HIGHLIGHTS OF PRESCRIBING INFORMATION. Available at: label (fda.gov) (Accessed: 13 December 2022).

• Acerta Pharma BV (2022) Acalabrutinib (ACP-196) in Combination With ACP-319, for Treatment of B-Cell Malignancies. Available at: Clinical Trial on Multiple Myeloma: Non-Hodgkins Lymphoma: B-All: Acalabrutinib: ACP-319 - Clinical Trials Registry - ICH GCP (Accessed: 13 December 2022).

• Adis Insight (2021) ACP 319. Available at: ACP 319 - AdisInsight (springer.com) (Accessed: 13 December 2022).

• Barr, P.M, Smith,S.D., Roschewski, M.J., O’Brien, S.M, Sharman, J.P., Melear, J.M, Patel,P., Calvo, R., Yang, H. and Spurgeon, S.E. (2022) ‘Phase 1/2 study of acalabrutinib and the PI3K delta inhibitor ACP-319 in relapsed/refractory B-cell NonHodgkin lymphoma.’ Leukemia & Lymphoma, 63:7(1728-1732) Available at: 10.1080/10428194.2022.2043301 (Accessed: 5 and 13 December 2022).

• Cancer research UK (2021) Risks and causes of chronic lymphocytic leukaemia (CLL). Available at: Risks and causes of chronic lymphocytic leukaemia | Cancer Research UK (Accessed: 13 December 2022).

• ∗2Clinical Trials.gov(2022) Acalabrutinib (ACP-196) in Combination with ACP-319,for Treatment of B-Cell Malignancies. Available at: Acalabrutinib (ACP-196) in Combination With ACP-319, for Treatment of B-Cell Malignancies - Study Results - ClinicalTrials.gov (Accessed: 13 December 2022).

• ClinicalTrials.gov(2022)Acalabrutinib in Combination with ACP-319, for Treatment of Chronic Lymphocytic Leukemia. Available at: Acalabrutinib in Combination With ACP319, for Treatment of Chronic Lymphocytic Leukemia - Full Text View - ClinicalTrials.gov (Accessed: 5 and 13 December 2022).

• Fenner, S.(2020) Safety in Lactation: Protein kinase inhibitors. Available at: Safety in Lactation: Protein kinase inhibitors – SPS - Specialist Pharmacy Service – The first stop for professional medicines advice (Accessed: 14 December 2022).

  
  

• Gilead(2014) Highlights of prescribing information. Available at: *zydelig_pi.pdf (gilead.com) (Accessed: 14 December 2022).

  
  

• Isoyama, S., Mori, S., Sugiyama, D., Kojima, Y., Tada,Y., Shitara,K., Hinohara,K.,Dan,S. and Nishikawa,H. (2021/2022) ‘Cancer immunotherapy with PI3K and PD-1 dual blockade via optimal modulation of T cell activation signal’ Journal for ImmunoTherapy of Cancer., Volume 9,Issue 8 (2021;9:e002279. ) Available at: 10.1136/ jitc-2020-002279 (Accessed: 13 December 2022).

• Kondĕlková, K., Vokurková, D., Krejsek,J., Borská, L., Fiala, Z. and Ctirad, A. (2010) ‘Regulatory T cells (TREG) and their roles in immune system with respect to immunopathological disorders. Acta Medica (Hradec Kralove), 53(2):73-7. Available at: 10.14712/18059694.2016.63 (Accessed:15 December 2022).

• MACMILLAN CANCER SUPPORT (2019) Breastfeeding and cancer treatments. Available at: Breastfeeding and cancer treatments | Macmillan Cancer Support (Accessed: 15 December 2022).

  
  

• Mishra, R., Patel, H., Alanazi,S., Kilroy, M.K and Garrett, J.T. (2021) ‘PI3K Inhibitors in Cancer: Clinical Implications and Adverse Effects’ Int J Mol Sci., 2021 Apr; 22(7):3464. Available at: 10.3390/ijms22073464 (Accessed:14 December 2022).

• Mozolewski,P., Moskot,M., Jakóbkiewicz-Banecka, J., Węgrzyn,G., Bocheńska,K., Banecki, B. and Gabig-Cimińska, M. (2017) ‘Nonsteroidal anti-inflammatory drugs modulate cellular glycosaminoglycan synthesis by affecting EGFR and PI3K signaling pathways’. Scientific reports, (7,Article number:43154) Available at: 10.1038/srep43154 (Accessed:14 December 2022).

  
  

• National Institute for Health and Care Excellence (no date) Pembrolizumab. Available at: Pembrolizumab | Drugs | BNF | NICE (Accessed: 10 and 13 December 2022).

• Niemann, C.S., Mora-Jensen, H.I, Dadashian, E.L., Krantz F., Covey, T., Chen, S., Chiorazzi,N., Izumi, R., Ulrich, R., Lannutti, B.J., Wiestner, A. and Herman, S.E.M (2017) ‘Combined BTK and PI3K Inhibition with Acalabrutinib and ACP-319 Improves Survival and Tumor Control in CLL Mouse Model.’ Clin Cancer Res., (Oct 1;23(19):5814-5823. Epub 2017 Jun 23.) Available at: 10.1158/1078-0432.CCR-17- 0650 (Accessed: 13 December 2022).

  
  

• Sabbah, D.A., Hajjo, R., Bardaweel, S.K and Zhong, H.A. (2021) ‘Phosphatidylinositol 3-kinase (PI3K) inhibitors: a recent update on inhibitor design and clinical trials (2016-2020)’ Expert Opin Ther Pat. (Oct;31(10):877-892. Epub 2021 May 16) Available at: 10.1080/13543776.2021.1924150 (Accessed: 7 and 13 December 2022).

  
  

• Uko, N.E, Güner, O.F., Matesic, D.F. and Bowen J.P. (2020) ‘Akt Pathway Inhibitors’ Curr Top Med Chem. (2020;20(10):883-900) Available at: 10.2174/1568026620666200224101808 (Accessed: 14 December 2022).

  
  

• Younes, A., Brody,J.,Carpio,C., Lopez-Guillermo, A., Ben-Yehuda, D., Ferhanoglu, B., Nagler, A., Ozcan, M., Avivi, I., Bosch, F., Barrigón, M.D.C., Hellmann, A., Kuss, B., Ma, D.D.F., Demirkan, F.,Yağci, M., Horowitz, N.A., Marlton, P., Cordoba, R. Wrobel, T., Buglio, D.,Streit, M., Hodkinson, B.P., Schaffer, M., Alvarez, J., Ceulemans,R., Balasubramanian, S., Jong, J.D Wang, S., Fourneau, N. and Jurczak, W. (2019) ‘Safety and activity of ibrutinib in combination with nivolumab in patients with relapsed non-Hodgkin lymphoma or chronic lymphocytic leukaemia: a phase 1/2a study' The Lancet Haemotology, Volume 6,Isuue 2 (E67-E78) Available at: https://doi.org/10.1016/S2352-3026(18)30217-5 (Accessed: 15 December 2022).

Assessed and Endorsed by the MedReport Medical Review Board