Patient case: 62-year-old male with cholangiocarcinoma; genetic feature: PIK3CA (1047H)

Clinical trial: PIPA: Combination of PI3 Kinase Inhibitors and PAlbociclib

Summary: Part A: This is a phase Ib trial combining the CDK4/6 inhibitor palbociclib with the PI3K inhibitors taselisib, or pictilisib. There are two treatment arms during the dose escalation phase where patients will receive either taselisib OR pictilisib in combination with palbociclib. Palbociclib, taselisib and pictilisib can all be given orally once daily with food, in a 21-days-on and 7-days-off schedule. Once the MTD is reached, the combination with the optimum safety and PK/PD profile will be taken forward to the dose expansion phase (Part B).
  Part B1: At the MTD dose expansion, fulvestrant will be administered in addition to palbociclib and taselisib or pictilisib orally once daily, in a 21-days-on and 7-days-off schedule in the ER+ve HER2-ve PIK3CA mutant breast cancer cohort. Fulvestrant will be given intramuscularly on Day 1, Day 15 in cycle one followed by Day 1 for all subsequent cycles.
  Part B2: At the MTD dose expansion, patients with PIK3CA mutant advanced solid tumours will be treated with palbociclib and taselisib or pictilisib orally once daily, in a 21-days-on and 7-days-off schedule.

Detailed description: This is a phase Ib trial of palbociclib in combination with either taselisib or pictilisib. The study will include a dose escalation phase (Part A), and an MTD dose expansion phase (Part B).
  Part A: will investigate escalating doses of palbociclib with either pictilisib or taselisib administered orally, continuously for 21 days out of a 28 day cycle in patients with advanced solid tumours recruited simultaneously into two parallel arms (up to 24 patients in each arm with a maximum of 48 patients in Part A).
  Once the MTD is determined the combination with the optimum safety and PK/PD profile as determined by the SRC will be taken forward to the dose expansion phase (Part B).
  Part B: The MTD dose expansion phase will be conducted using the optimal combination from Part A in two parallel arms as follows:
  B1: Patients (n=25) with PIK3CA mutant ER + HER2-ve advanced breast cancers will be treated with a triplet combination of palbociclib and either taselisib or pictilisib along with fulvestrant. Part B1 will require at least two of the first 15 patients to respond to progress to recruit the full 25 patients.
  B2: Patients (n=20) with PIK3CA mutant advanced solid tumours including at least 8 patients with PIK3CA mutant ER negative and/or HER2 positive breast cancers will be treated with the doublet combination of palbociclib and either taselisib or pictilisib. Other cancers with relevant genetic aberrations (e.g. KRAS mutations) may be considered, depending on emerging preclinical and clinical data on these novel antitumour agents.
  In total, it is expected that a minimum of 70 and up to a maximum of 93 patients will be enrolled into the trial, the final number will depend on the number of dose escalations required to reach DLT. If < 48 patients are enrolled in Part A, investigators will be permitted to enrol > 45 patients in Part B, providing the maximum number of patients remains ≤93 patients across the study.
  The anticipated accrual rate during the dose escalation phase is estimated at 2 patients per month. Accrual in the expansion phase is estimated at 4 patients per month across 2 centres. It is expected that the trial will have a duration of recruitment of 12 to 24 months.

Eligibility: Inclusion Criteria:
  1. Part A (dose escalation):
  Patients with histologically or cytologically confirmed malignant advanced solid tumours refractory to standard therapy or for which no suitable effective standard therapy exists, including, but not limited to patients with PIK3CA mutant cancers, or those with somatic mutations or other aberrations known to result in a hyperactivated PI3K-AKT pathway.
  Advanced breast cancer with the following features:
  -  ER+ve breast cancer that has progressed on at least one line of prior endocrine therapy, or
  -  PIK3CA mutant breast cancer progressed on at least one line of prior endocrine therapy or chemotherapy
  -  breast cancer refractory to standard treatment
  Part B (dose expansion):
  Patients with histologically or cytologically advanced solid tumours who have progressed on at least one prior chemotherapy regimen for advanced cancer with a PIK3CA mutation detected from tumour and/or circulating tumour DNA. Patients with HER2 positive breast cancer should have progressed on at least two prior HER2 directed therapies for advanced breast cancer.
  Cohort B1: ER+ve and HER2-ve post-menopausal breast cancer that has progressed on at least one prior hormone therapy for advanced breast cancer.
  Cohort B2: Advanced PIK3CA mutant solid tumours, including but not limiting to triple negative and/or HER2 positive breast cancers and lung, head and neck cancers.
  NB. PIK3CA mutation may be assessed in archival tumour samples, fresh tumour samples, or in circulating free DNA extracted from plasma or serum. A mutation will be considered pathogenic if described to be recurrent somatic mutation in COSMIC (http://cancer.sanger.ac.uk/cancergenome/projects/cosmic/). Other cancers with relevant genetic aberrations (e.g. KRAS mutations) may be considered, depending on emerging preclinical and clinical data on these novel antitumour agents
  2. Part A: Measurable disease as assessed by RECIST 1.1 OR evaluable disease. Part B1: Measurable disease as assessed by RECIST 1.1 Part B2: Measurable disease as assessed by RECIST 1.1 OR evaluable disease
  3. Life expectancy of at least 12 weeks
  4. World Health Organisation (WHO) performance status of 0-1 with no significant deterioration over the previous 2 weeks
  5. Haematological and biochemical indices within the ranges shown below. These measurements must be performed within one week (Day -7 to Day 1) before the patient goes in the trial.
  Haemoglobin (Hb) ≥ 10.0 g/dL Absolute neutrophil count ≥ 1.5 x 109/L Platelet count ≥ 100 x 109/L Serum bilirubin ≤ 1.5 x upper limit of normal (ULN) except for patients with documented Gilberts' disease Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x (ULN) unless raised due to tumour in which case up to 5 x ULN is permissible
  Creatinine:
  If creatinine > 1.5 times ULN then:
  Either:
  Calculated creatinine clearance ≥ 50 mL/min (uncorrected value)
  Or:
  Isotope clearance measurement ≥ 50mL/min (corrected)
  Coagulation:
  INR <1.5 APTT <1.5x ULN
  6. Female patients with reproductive potential must have a negative urine or serum pregnancy test within 7 days prior to start of trial. Both women and men must agree to use a medically acceptable method of contraception throughout the treatment period and for 3 months after discontinuation of treatment.
  7. 18 years of age or over with written (signed and dated) informed consent and be capable of co-operating with treatment and follow-up.
  Exclusion Criteria:
  1. Radiotherapy (except for palliative reasons), endocrine therapy, immunotherapy or chemotherapy during the previous four weeks (six weeks for nitrosoureas, Mitomycin-C) and 4 weeks for investigational medicinal products before treatment, except for hormonal therapy with luteinizing hormone-releasing hormone (LHRH) analogues for medical castration in patients with castrate resistant prostate cancer, which are permitted, and bisphosphonates or RANK ligand antagonists that are permitted for the management of bone metastases. Palliative radiotherapy is acceptable if given for bony metastases as long as these are not indicative of disease progression. Study drug must be stopped 3 days before radiotherapy and restarted within 28 days, as long as bone marrow function has returned to normal.
  2. Patients with prior exposure to both a CDK4/6 inhibitor and a PI3K/ATK/mTOR inhibitor are excluded from the study. Patients with prior exposure to either a PI3K/AKT/mTOR pathway inhibitor OR a CDK4/6 inhibitor (but not both) are allowed entry into the trial provided that adverse effects have recovered to grade 1 or less. Prior exposure to fulvestrant is permitted.
  3. Clinically significant abnormalities of glucose metabolism as defined by any of the following:
  -  Diagnosis of diabetes mellitus types I or II (irrespective of management).
  -  Glycosylated haemoglobin (HbA1C) ≥7.0% at screening
  -  Fasting Plasma Glucose ≥ 8.3mmol/L at screening. Fasting is defined as no caloric intake for at least 8 hours.
  4. DLCO ≤ 50% of predicted value corrected for hematocrit prior to initiation of study treatment.
  5. On-going toxic manifestations of previous treatments ≥ grade 1. Exceptions to this are alopecia or certain other toxicities, which in the opinion of the Investigator should not exclude the patient.
  6. History of malabsorption syndrome or other condition that would interfere with enteral absorption. For example active intestine inflammation (e.g., Crohn's disease or ulcerative colitis) requiring immunosuppressive therapy.
  7. History of inflammatory bowel disease (e.g. Crohn's disease or ulcerative colitis)
  8. Inability or unwillingness to swallow pills, or (for patients receiving fulvestrant) receive IM injections.
  9. Known untreated or active central nervous system (CNS) metastases (progressing or requiring corticosteroids for symptomatic control). Patients with a history of treated CNS metastases are eligible, provided they meet all of the following criteria:
  -  Evaluable or measurable disease outside the CNS is present.
  -  Radiographic demonstration of improvement upon the completion of CNS-directed therapy and no evidence of interim progression between the completion of CNS-directed therapy and the baseline disease assessment for at least 28 days.
  -  Not requiring dexamethasone treatment
  10. Major surgery (excluding minor procedures, e.g. placement of vascular access) within 4 weeks of the first dose of study treatment
  11. Ability to become pregnant (or already pregnant or lactating). However, those female patients who have a negative serum or urine pregnancy test before enrolment and agree to use two highly effective forms of contraception (oral, injected or implanted hormonal contraception and condom, have a intra-uterine device and condom, diaphragm with spermicidal gel and condom) for four weeks before entering the trial, during the trial and for six months afterwards are considered eligible.
  12. Male patients with partners of childbearing potential (unless they agree to take measures not to father children by using one form of highly effective contraception [condom plus spermicide] during the trial and for six months afterwards). Men with pregnant or lactating partners should be advised to use barrier method contraception (for example, condom plus spermicidal gel) to prevent exposure to the foetus or neonate.
  13. At high medical risk because of severe or uncontrolled systemic disease, such as:
  uncontrolled hypertension, symptomatic congestive heart failure ≥ class 2 (refer to appendix 4 for grading), unstable angina pectoris, stroke or myocardial infarction within 6 months, serious cardiac arrhythmia requiring treatment, with the exceptions of atrial fibrillation and paroxysmal supraventricular tachycardia or conduction abnormality that has been treated and for which the patient is no longer at risk for serious arrhythmia (e.g., Wolff-Parkinson-White syndrome treated with surgical ablation)
  14. Clinically significant history of liver disease, including cirrhosis, current alcohol abuse, or current known active infection with hepatitis B virus, or hepatitis C virus.
  Active infection is defined as requiring treatment with antiviral therapy or presence of positive test results for Hepatitis B (Hepatitis B surface antigen [HBsAg] and/or total Hb core antibody [anti-HBc]) or Hepatitis C (Hepatitis C virus [HCV] antibody). Unless required by local regulations, patients are not required to have HIV, HCB, or HCV assessments at screening if these assessments have not been previously performed.
  Patients who are positive for anti-HBc are eligible only if testing is also positive for Hepatitis B surface antibody [HbsAb] and polymerase chain reaction (PCR) is negative for HBV DNA.
  Patients who are positive for HCV serology are eligible only if testing for HCV RNA is negative.
  15. Immunocompromised status due to current known active infection with HIV or due to the use of immunosuppressive therapies for other conditions
  16. Need for current chronic corticosteroid therapy, specifically dexamethasone or ≥ 10 mg of prednisone per day or an equivalent dose of other anti inflammatory corticosteroids. Stable use (i.e., no change in dose within 1 month prior to Day 1 of Cycle 1) of inhaled corticosteroids is allowed.
  17. Prior bone marrow transplant or extensive radiotherapy to greater than 25% of bone marrow within eight weeks.
  18. Is a participant or plans to participate in another interventional clinical trial, whilst taking part in this Phase I study. Participation in an observational trial would be acceptable.
  19. Current malignancies of other types, with the exception of adequately treated cone-biopsied in situ carcinoma of the cervix uteri and basal or squamous cell carcinoma of the skin. Cancer survivors, who have undergone potentially curative therapy for a prior malignancy, have no evidence of that disease for 3 years or more and are deemed at negligible risk for recurrence, are eligible for the trial.
  20. Any other condition which in the Investigator's opinion would not make the patient a good candidate for the clinical trial.

Relevance to patient case: possibly relevant