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

Clinical trial: Triapine With Chemotherapy and Radiation Therapy in Treating Patients With IB2-IVA Cervical or Vulvar Cancer

Summary: This phase I trial studies the side effects and best dose of triapine when given with radiation therapy and cisplatin in treating patients with stage IB2-IVA cervical or vulvar cancer. Triapine may stop the growth of cancer cells by blocking an enzyme needed for cell growth. Cisplatin is a drug used in chemotherapy that kills cancer cells by damaging their deoxyribonucleic acid (DNA) and stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells and shrink tumors. Adding triapine to standard treatment with cisplatin and radiation therapy may kill more cancer cells.

Detailed description: PRIMARY OBJECTIVES:
  I. To determine the maximum tolerable dose (MTD) and recommended phase II dose (RP2D) of oral triapine when used in combination with cisplatin plus radiation therapy.
  II. To determine the oral bioavailability of triapine.
  SECONDARY OBJECTIVES:
  I. To compare the pharmacokinetics (PK) of oral and intravenous triapine. II. To determine metabolic complete response (mCR) rate of oral triapine in combination with cisplatin chemoradiation using fludeoxyglucose F 18 (18F-FDG)-positron emission tomography (PET) computed tomography (CT) at post-therapy (3-months).
  TERTIARY OBJECTIVES:
  I. To determine whether the overexpression of ribonucleotide reductase (RR) in archival tumor tissue is correlated with the antitumor activity of triapine.
  II. To determine the effect of combined modality treatment on activation of ATM serine/threonine kinase (ATM) and H2A histone family, member X (H2AX) and possibly other markers in peripheral blood.
  OUTLINE: This is a dose escalation study of triapine.
  Patients undergo pelvic external beam radiation therapy (EBRT) or intensity modulated radiation therapy (IMRT) 5 days per week for 5 weeks (25 fractions) with a 3-day boost in week 6, and 1 or 3 applications of low dose rate (LDR) brachytherapy in week 6 or 5 fractions of high dose rate (HDR) brachytherapy at week 4 or 5. Patients also receive triapine intravenously (IV) over 2 hours on days 1 and 11 and orally (PO) on days 2-5, 8-10, 12, 15-19, 22-26, and 29-33 within 90 minutes after pelvic irradiation, and cisplatin IV over 90-120 minutes once weekly for 5 weeks (days 2, 9, 16, 23, and 30). Treatment continues in the absence of disease progression or unacceptable toxicity.
  After completion of study treatment, patients are followed up for 3 months.

Eligibility: Inclusion Criteria:
  -  Pathologic diagnosis of stage IB2-IVA squamous, adenocarcinoma, or adenosquamous carcinoma of the uterine cervix or stage II-IVA squamous or adenocarcinoma of the vulva that is not amenable to curative surgical resection alone
  -  Patient must be able to tolerate imaging requirements of an 18-FDG-PET-CT scan
  -  Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2
  -  Life expectancy greater than 6 months
  -  Absolute neutrophil count (ANC) >= 1.5 x 10^9/L
  -  Platelets >= 100 x 10^9/L
  -  Hemoglobin (Hgb) >= 9.0 g/dL
  -  International normalized ratio (INR) =< 2
  -  Serum creatinine =< 1.5 x upper limit of normal (ULN)
  -  Total serum bilirubin =< 1.5 x ULN (in patients with known Gilbert syndrome, a total bilirubin =< 3.0 x ULN, with direct bilirubin =< 1.5 x ULN)
  -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN
  -  Able to take oral medication and has no history of gastric surgery or pathology
  -  Not pregnant and not breastfeeding; women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; patient must have documented negative urine pregnancy test must be resulted within 7 days before initiating protocol therapy; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately; breastfeeding should be discontinued if the mother is treated with triapine; potential risks may also apply to other agents used in this study
  -  Healthy human immunodeficiency virus (HIV)-infected patients are eligible, provided that they meet all the other study criteria in addition to the following:
  -  Cluster of differentiation (CD)4+ cell count >= 250/mm^3
  -  Not on antiretroviral therapy affecting cytochrome P450 (p450) metabolism
  -  HIV viral loads undetectable by standard clinical tests
  -  Able to understand and willingness to sign a written informed consent document
  Exclusion Criteria:
  -  Patients with other active invasive malignancies will be excluded; patients with prior malignancies will be excluded (except [1] non-melanoma skin cancer or prior in situ carcinoma of the cervix; [2] patients with other invasive malignancies who had [or have] cancer present within the last five years)
  -  Patients with hypermetabolic para-aortic disease identified on baseline 18-FDG-PET-CT
  -  No prior pelvic radiation therapy or chemotherapy
  -  Patients receiving any other investigational agents
  -  Patients with known glucose-6-phosphate dehydrogenase deficiency (G6PD) are excluded; pre-registration testing for G6PD is at the investigator's discretion and is not required for study enrollment
  -  Patients taking medications affecting cytochrome P450 (CYP-450) metabolism
  -  Patients with known brain metastases are excluded
  -  History of allergic reactions attributed to compounds of similar chemical or biologic composition to triapine or cisplatin
  -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection; symptomatic congestive heart failure; unstable angina pectoris; cardiac arrhythmia; known inadequately controlled hypertension; significant pulmonary disease including dyspnea at rest, patients requiring supplemental oxygen, or poor pulmonary reserve; or psychiatric illness/social situations that would limit compliance with study requirements
  -  Patients with uncontrolled diabetes mellitus (fasting blood glucose controlled by medication, =< 200 mg/dL allowed)
  -  Known HIV-positive patients receiving combination antiretroviral therapy are ineligible; however, HIV testing is not required for study enrollment and optional

Relevance to patient case: not relevant