Osimertinib Plus Capivasertib in NSCLC With PIK3CA/AKT1/PTEN Alterations Following Prior 1L Osimertinib

This is a two-stage study, consisting of Phase Ib dose-escalation, Phase IIa dose expansion. Safety will be intensively monitored in Part A. If RCD (Recommended combined dose) was not reached in Part A, Part B (dose expansion phase) would not be initiated. If RCD was reached in Part A, eligible patients in Part B will be enrolled and receive Osimertinib (80mg QD, continuously) plus Capivasertib (RCD, orally BID from day1-day 4 in 7-day cycle , 4 days on /3 days off) till disease progression (PD) or unacceptable toxicity, with the aim to further evaluate the safety, tolerability and efficacy in terms of ORR, DCR, DOR, PFS and OS.

All participants (18 and above) will undergo screening (Day -28 to -1), treatment period (starting from Day 1) and post-intervention follow-up period (end of treatment visit, 30-day safety follow-up and survival follow-up).

Dose escalation(Part A) will follow the classic "3+3" schema. The DLT observation period is 28 days post first dose of study treatment. Dose escalation will occur only after DLT observation period is completed for a minimum of 3 participants, relevant data has been reviewed within the Safety Review Committee (SRC), and the SRC approves dose escalation.

Inclusion criteria

Informed consent

• Provision of signed and dated, written informed consent form (ICF) prior to any mandatory and non-mandatory study-specific procedures, sampling and analyses

Age

• Male or female age ≥18 years at the time of signing the ICF.

Type of participant and disease characteristics

• Histologically or cytologically confirmed non-squamous locally advanced or metastatic NSCLC which is not amenable to curative therapy.
• Documented EGFR sensitive mutations (exon19 deletion, L858R mutation) prior to the first-line EGFR-TKI therapy.
• Documented radiologic progression on first-line treatment with Osimertinib monotherapy or Osimertinib plus chemotherapy:

• Participants treated with Osimertinib in the adjuvant setting can be included if progression occurred < 6 months after last dose.
• Participants must be immunotherapy (i.e., programmed cell death protein 1 [PD-1] inhibitor, programmed cell death protein 1 ligand 1 [PD-L1] inhibitor, Cytotoxic T-lymphocyte associated protein 4 inhibitor) naïve in the metastatic setting.
• Prior immunotherapy in the neoadjuvant or adjuvant setting is acceptable providing treatment was completed more than 6 months before metastatic/recurrent disease was diagnosed.
• Mandatory provision of the required number of FFPE tumour tissue samples for PIK3CA mutations and/or AKT1 mutations and/or PTEN loss-of-function (LOF) mutations testing, which fulfils the following requirements:

• Obtained following progression on previous Osimertinib monotherapy or Osimertinib plus chemotherapy as first-line treatment.
• Specimen to meet the requirements defined in the Central Laboratory Manual and Diagnostic Testing Manual.
• Have PIK3CA and/or AKT1 and/or PTEN alterations as determined by NGS testing by a sponsor designated central laboratory on tumour specimen collected following progression on prior Osimertinib treatment.
• At least one lesion, not previously irradiated, not biopsied during the screening period, that can be accurately measured at baseline as ≥ 10 mm in the longest diameter (except lymph nodes which must have short axis ≥ 15 mm) with CT or MRI, which is suitable for accurate repeated measurements. If only one measurable lesion exists, it is acceptable to be used if baseline tumour assessment scans are done at least 14 days after the screening tumour specimen collection is performed.
• Adequate bone marrow reserve and organ function as follows:

• Absolute neutrophils count (ANC) ≥1.5x109/L.
• Platelets count ≥100x109/L.
• Haemoglobin (Hb) ≥90g/L.
• Total bilirubin ≤1.5 times upper limit of normal (ULN) or ≤3 times ULN in the presence of documented Gilbert's Syndrome (unconjugated hyperbilirubinaemia) or liver metastases.
• Alanine transaminase (ALT) and aspartate transaminase (AST) ≤2.5ULN (or ≤5 ULN in the presence of liver metastases).
• Serum Creatinine ≤1.5 ULN or creatinine clearance (CCr) ≥50mL/min (measured or calculated by Cockcroft and Gault equation); confirmation of creatinine clearance is only required when creatinine is >1.5 times ULN.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Patients with hepatitis B virus (HBV) are only eligible for inclusion if they meet all the following criteria:

• Demonstrated absence of hepatitis C virus (HCV) co-infection or history of HCV co-infection
• Demonstrated absence of human immunodeficiency virus (HIV) infection
• Participants with active HBV infection are eligible if they are:
• Receiving anti-viral treatment for at least 6 weeks prior to study treatment, HBV DNA is suppressed to <100 IU/mL and transaminase levels are below ULN.
• Participants with a resolved or chronic HBV infection are eligible if they are:
• Negative for HBsAg and positive for hepatitis B core antibody [anti-HBc IgG or total anti-HBc Ab]. In addition, patients should be referred to a local hepatologist and treated as per local guidelines.

or

• Positive for HBsAg, but for > 6 months have had transaminases levels below ULN and HBV DNA levels below <100 IU/mL or below the detectable limit of locally available test kit (i.e., are in an inactive carrier state). In addition, patients must be receiving anti-viral prophylaxis for 2-4 weeks prior to study treatment.

Patients with HIV are only eligible for inclusion if they meet all the following criteria:

• Demonstrated absence of HBV/ HCV co-infection
• Undetectable viral RNA load for 6 months
• CD4+ count of >350 cells/µL
• No history of AIDS-defining opportunistic infection within the past 12 months

Stable for at least 4 weeks on the same anti-HIV medications.

• Ability to swallow and retain oral medications.
• Willingness and ability to comply with study and follow-up procedures. Reproduction
• Females must be using highly effective contraceptive measures, and must have a negative pregnancy test prior to start of dosing if of child-bearing potential, or must have evidence of non-child-bearing potential by fulfilling one of the following criteria at screening:

• Post-menopausal defined as aged 50 years or more and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments.
• Women under 50 years old would be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and with LH and FSH levels in the post-menopausal range for the institution.
• Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation.

Further information in Appendix C (Definition of Women of Childbearing Potential and Acceptable Contraceptive Methods).

• Male participants must be willing to use barrier contraception. Exclusion criteria

Medical conditions

• Patients harbouring concurrent actionable driver mutations with locally approved targeted therapies (e.g., MET amplification) will be excluded.
• Past medical history of interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD.
• Clinically significant abnormalities of glucose metabolism as defined by any of the following:

• Fasting glucose ≥7.0 mmol/L (126 mg/dL) or 2 hours after glucose solution intake, blood glucose ≥11.1 mmol/L (200 mg/dL).
• HbA1c ≥8.0% (63.9 mmol/mol) at screening. Note: for any patient with evidence of impaired glucose control or insulin resistance refer to the Capivasertib Toxicity Management Guidelines.
• Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, which in the investigator's opinion makes it undesirable for the patient to participate in the trial or which would jeopardize compliance with the protocol, or active infection (e.g. patients receiving treatment for infection) including hepatitis C and human immunodeficiency virus (HIV), or active uncontrolled hepatitis B virus (HBV) infection, or active tuberculosis infection (clinical evaluation that may include clinical history, physical examination and radiographic findings, or tuberculosis testing in line with local practice) .

• Screening for chronic conditions is not required.
• Spinal cord compression, leptomeningeal metastasis, or brain metastases unless asymptomatic, stable, and not requiring steroids for at least 4 weeks prior to start of study intervention.
• Any of the following cardiac criteria:

• Mean resting corrected QTc >470 msec, obtained from triplicate electrocardiograms (ECGs), using the screening clinic ECG machine derived QTc value.
• History of QT prolongation associated with other medications that required discontinuation of that medication.
• Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG e.g., complete left bundle branch block, third degree heart block and second-degree heart block.
• Medical history significant for arrhythmia (e.g., multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (Common Terminology Criteria for Adverse Events [CTCAE] Grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Participants with atrial fibrillation controlled by medication or arrhythmias controlled by pacemakers may be permitted to enter the study based on the Investigator judgement with cardiologist consultation recommended.
• Patient with any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as electrolyte abnormalities including:

• Hypokalaemia|* ≥ CTCAE Grade 2.
• Heart failure, congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives or any concomitant medication known to prolong the QT interval and cause Torsade de Pointes.
• Correction of electrolyte abnormalities should be documented prior to first dose.
• Experience of any of the following procedures or conditions in the preceding 6 months: coronary artery bypass graft, angioplasty, vascular stent, myocardial infarction, angina pectoris, congestive heart failure New York Heart Association (NYHA) Grade 2.
• History of another primary malignancy except for malignancy treated with curative intent with no known active disease ≥2 years before the first dose of investigational product (IP) and of low potential risk for recurrence. Exceptions include adequately resected non-melanoma skin cancer and curatively treated in situ disease.
• Any unresolved toxicities from prior therapy greater than CTCAE grade 1 at the time of starting study treatment except for alopecia and grade 2 prior platinum-therapy related neuropathy. Participants with irreversible toxicity that is not reasonably expected to be exacerbated by study intervention in the opinion of the Investigator may be included (e.g., hearing loss).
• Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption, distribution, metabolism, or excretion of IP.
• Any other disease, physical examination finding, or clinical laboratory finding that, in the investigator's opinion, gives reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, may affect the interpretation of the results, render the patient at high risk from treatment complications or interferes with obtaining informed consent.

Prior/concomitant therapy

• Prior or current treatment with a third-generation EGFR-TKI other than Osimertinib.
• Prior or current treatment with any PI3K/AKT pathway inhibitors, including but not limited to: Capivasertib or other AKT inhibitors, PI3K inhibitors, or agents targeting key nodes in this pathway (e.g., PTEN-modulating therapies).
• Concurrent use of herbal or natural products intended as treatment or prophylaxis for any type of cancer.
• Wide field radiotherapy (including therapeutic radioisotopes such as strontium 89) administered ≤ 28 days or limited field radiation for palliation ≤ 14 days prior to starting study intervention or has not recovered from side effects of such therapy.
• Major surgery or significant traumatic injury within 4 weeks of the first dose of study intervention or an anticipated need for major surgery during the study. Procedures such as placement of vascular access, biopsy via mediastinoscopy or biopsy via video assisted thoracoscopic surgery (VATS) are permitted.
• Systemic therapy: Prior exposure to any anti-cancer agents other than those specified in the protocol (e.g. hormonal therapy such as luteinizing hormone releasing hormone [LHRH] agonists) without appropriate washout period before enrolment, for example, enrolment within 3 half-lives of a small molecule anti-cancer agent, or within 4 weeks for any antibody-based anticancer agents.
• Participants currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be strong inducers (at least 3-week prior), moderate inducers (at least 2-week prior) or strong inhibitors of CYP3A4 (at least 2-week prior). All participants must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer or inhibitor effects on CYP3A4. Any concomitant medication that may interfere with Osimertinib safety and efficacy based on the prescribing information of Osimertinib and local clinical guidelines.

Prior/concurrent clinical study experience

• Participation in another clinical study with a study intervention or investigational medicinal device administered in the 4 weeks prior to first dose of study intervention or concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study.

Other exclusions

• History of hypersensitivity to active or inactive excipients of Capivasertib or Osimertinib or drugs with a similar chemical structure or class.
• Women who are currently pregnant (confirmed with positive pregnancy test) or breast-feeding or planning to become pregnant.
• Involvement in the planning and/or conduct of the study (applies to both Investigator staff and/or staff at the study site).