Patient case: 26-year-old female with Cervical cancer. Genetic variant: STK11. Other conditions: None.

Clinical trial: ENGOT-cx1/BGOG-cx1: 3 Weekly Carboplatin/Paclitaxel With or Without Nintedanib in Cervix Cancer

Summary: Indication:
  Treatment of subjects with advanced (FIGO stage IVB) or recurrent cervical cancer, prior radiochemotherapy or neo-adjuvant chemotherapy is allowed.
  Study design:
  This is a phase II randomized, double blind and placebo controlled trial evaluating the efficacy of Nintedanib/placebo in combination with the standard of 6 cycles 3 weekly carboplatin and paclitaxel followed by Nintedanib/placebo maintenance in the treatment of patients with advanced or recurrent cervical cancer.
  A total of 120 patients will be randomized between the experimental and control arm in a 1:1 ratio. Randomization will be stratified for 1previous therapy (chemo-radiotherapy or neoadjuvant chemotherapy: no, >6 months since last platin course) and 2disease status (Stage IVB primary versus recurrent disease).
  Experimental arm: Subjects will receive 6 cycles of 3-weekly carboplatin (AUC 5) + paclitaxel (175 mg/m2) and Nintedanib 200 mg BID followed by Nintedanib maintenance until progression or for a total maximum duration of 120 weeks.
  Control arm: Subjects will receive 6 cycles of 3-weekly carboplatin (AUC 5) + paclitaxel (175 mg/m2) and placebo 200 mg BID followed by placebo maintenance until progression or for a total maximum duration of 120 weeks.
  Subjects without evidence of disease progression after completion or discontinuation of the study treatment will be followed until radiographic disease progression, withdrawal of consent or death.


Eligibility: Inclusion Criteria:
  -  Female subjects more than 18 years of age
  -  Histologically or cytologically confirmed advanced ([FIGO] stage IVB), or recurrent/persistent squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix will be eligible.
  -  No prior chemotherapy for recurrent cervical cancer.
  -  Prior concomitant cisplatinum chemotherapy during radiotherapy is allowed (except if recurrence is within 6 months after the end of the platinum containing chemotherapy).
  -  Cases primarily treated with neoadjuvant chemotherapy before radical local surgery are eligible at the time of first recurrence. (except if recurrence is within 6 months after the end of the platinum containing chemotherapy).
  -  Cases primarily treated with neoadjuvant chemotherapy before radical local surgery followed by adjuvant radiochemotherapy are eligible at the time of first recurrence (except if recurrence is within 6 months after the end of the platinum containing chemotherapy).
  -  Cases primarily treated with neoadjuvant chemotherapy before radical local surgery followed by adjuvant radiotherapy are eligible at the time of first recurrence (except if recurrence is within 6 months after the end of the platinum containing chemotherapy).
  -  Life expectancy at least 3 months.
  -  ECOG Performance status score of 0 or 1
  -  At least one measurable lesion according to RECIST 1.1 criteria
  -  Signed and dated written informed consent prior to admission to the study in accordance with ICH-GCP guidelines and to the local legislation
  Exclusion Criteria:
  -  Prior chemotherapy except platin-based concomitant chemotherapy during radiotherapy
  -  Prior chemotherapy for advanced (FIGO stage IVB) or recurrent disease except as mentioned in point 3.1.3.
  -  Prior treatment with nintedanib or any other VEGFR inhibitor.
  -  Known hypersensitivity to the trial drugs or to their excipients.
  -  Brain or leptomeningeal metastases.
  -  Centrally located tumors with radiographic evidence (CT or MRI) of local invasion of major blood vessels.
  -  Tumor infiltrating the mucosa of the bowel or bladder, or known fistulas between the tumor and the gastrointestinal or urinary tract.
  -  Treatment with other investigational drugs or treatment in another clinical trial within the past 4 weeks before start of therapy or concomitantly with the trial.
  -  Therapeutic anticoagulation or anti-platelet therapy is not allowed, unless the patient is on stable anti-coagulation
  -  Major injuries within the past 10 days prior to start of study treatment with incomplete wound healing and/or planned surgery during the on-treatment study period.
  -  History of clinically significant haemorrhagic or thromboembolic event in the past 6 months.
  -  Known inherited predisposition to bleeding or thrombosis.
  -  Significant cardiovascular diseases ( i.e. uncontrolled hypertension, unstable angina within the past 6 months, history of infarction within the past 6 months prior to start of study treatment, congestive heart failure > NYHA II, serious cardiac arrhythmia, pericardial effusion).
  -  History of a cerebral vascular accident, transient ischemic attack or subarachnoid haemorrhage within the past 6 months.
  -  Abnormal renal, liver or bone marrow function defined as:
  -  Proteinuria CTCAE grade 2 or greater
  -  Creatinin > 2 ULN or GFR < 30 ml/min
  -  Hepatic function: total bilirubin outside of normal limits; ALT or AST > 1.5 ULN in pts without liver metastasis. For Pts with liver metastases: total bilirubin outside of normal limits, ALT or AST > 2.5 ULN
  -  Coagulation parameters: International normalised ratio (INR) > 2, prothrombin time (PT) and partial thromboplastin time (PTT) > 50% of deviation of institutional ULN
  -  Absolute neutrophil count ( ANC) < 1500/µl, platelets < 100000/µl, haemoglobin < 9.0 g/dl
  -  Other malignancies within the past 3 years or other malignancy with recurrence in the past 3 years or with high risk of recurrence in the first year. In exception to this rule, the following malignancies may be included: non-melanomatous skin cancer (if adequately treated) , any premalignant (e.g. in situ) carcinoma, or basocellular carcinoma.
  -  Active serious infections in particular if requiring systemic antibiotic or antimicrobial therapy.
  -  Active or chronic hepatitis C and/or B infection or known HIV infection.
  -  Gastrointestinal disorders or abnormalities that would interfere with absorption of the study drug.
  -  Serious illness or concomitant non-oncological disease such as neurologic, psychiatric, infectious disease or active ulcers (gastro-intestinal tract, skin) or laboratory abnormality that may increase the risk associated with study participation or study drug administration and in the judgment of the investigator would make the patient inappropriate for entry into the study.
  -  Patients of child-bearing potential who are sexually active and unwilling to use a medically acceptable method of contraception (e.g. such as implants, injectables, combined oral contraceptives, some intrauterine devices or vasectomized partner or sexual abstinence for participating females) during the trial and for at least three months after end of active therapy.
  -  Pregnancy or breast feeding, female patients must have a negative pregnancy test (β-HCG test in urine or serum) prior to commencing study treatment, if applicable.
  -  Psychological, familial, sociological or geographical factors potentially hampering compliance with the study protocol and follow-up schedule.
  -  Active alcohol or drug abuse.

Relevance to patient case: not relevant