Triapine With Chemotherapy and Radiation Therapy in Treating Patients With IB2-IVA Cervical or Vaginal Cancer

NCT02595879Active, Not RecruitingPHASE1INTERVENTIONAL

Summary

Key Facts

Lead Sponsor

National Cancer Institute (NCI)

Enrollment

21

Start Date

2019-09-18

Completion Date

2023-06-04

Study Type

INTERVENTIONAL

Official Title

Phase I Dose-Escalation Bioavailability Study of Oral Triapine in Combination With Concurrent Chemoradiation for Locally Advanced Cervical Cancer (LACC) and Vaginal Cancer

Interventions

Biospecimen CollectionBrachytherapyCisplatinComputed TomographyExternal Beam Radiation TherapyFludeoxyglucose F-18High-Dose Rate BrachytherapyIntensity-Modulated Radiation TherapyMagnetic Resonance ImagingPharmacological StudyPositron Emission TomographyTriapine

Conditions

Advanced Cervical AdenocarcinomaAdvanced Cervical Adenosquamous CarcinomaAdvanced Cervical Squamous Cell CarcinomaAdvanced Vaginal AdenocarcinomaAdvanced Vaginal Adenosquamous CarcinomaAdvanced Vaginal Squamous Cell CarcinomaStage IB2 Cervical Cancer AJCC v6 and v7Stage II Cervical Cancer AJCC v7Stage II Vaginal Cancer AJCC v6 and v7Stage III Vaginal Cancer AJCC v6 and v7Stage IIIB Cervical Cancer AJCC v6 and v7Stage IVA Cervical Cancer AJCC v6 and v7Stage IVA Vaginal Cancer AJCC v6 and v7

Eligibility

Age Range

18 Years+

Sex

FEMALE

Inclusion Criteria:

* Patient has a new, untreated histologic diagnosis of stage IB2 (\> 5 cm), II, IIIB, IIIC or IVA squamous, adenocarcinoma, or adenosquamous carcinoma of the uterine cervix or stage II-IVA squamous, adenocarcinoma, or adenosquamous carcinoma of the vagina not amenable to curative surgical resection alone; the presence or absence of lymph node metastasis will be based on pre-therapy 18F-FDG PET/CT; the patient must be able to tolerate imaging requirements of an 18F-FDG PET/CT scan
* Age \>= 18 years old
* 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) \>= 10.0 g/dL (blood transfusions to reach this amount are allowed)
* Serum creatinine =\< 1.5 mg/dL to receive weekly cisplatin

  * If serum creatinine is between 1.5 and 1.9 mg/dL, patients are eligible for cisplatin if the estimated creatinine clearance (CCr) is \> 30 ml/min (for the purpose of estimating the CCr, the formula of Cockcroft and Gault for females should be used)
* Total serum bilirubin =\< 1.5 x upper limit of normal (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
* Not pregnant and not breastfeeding; the effects of triapine on the developing human fetus are unknown; for this reason as well as because heterocyclic carboxaldehydethiosemicarbazones and radiation are known to be teratogenic, women of child-bearing potential and men must agree to use two forms of 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; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with triapine, breastfeeding should be discontinued if the mother is treated with triapine; these potential risks may also apply to other agents used in this study
* For HIV and hepatitis B/C (HEPB/C):

  * HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for the dose escalation portion of this trial; for those patients who are enrolled in the HIV positive (+) expansion cohort, they must be HIV infected and be on retroviral therapy with an undetectable viral load within 6 months of enrollment
  * For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
  * Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured; for patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
* Able to understand and willingness to sign a written informed consent document

Exclusion Criteria:

* Patient has had a prior invasive malignancy diagnosed within the last three years (except \[1\] non-melanoma skin cancer or \[2\] prior in situ carcinoma of the cervix)
* Patients are excluded if they have received prior pelvic radiotherapy for any reason that would contribute radiation dose that would exceed tolerance of normal tissues at the discretion of the treating physician
* Patients receiving any other investigational agents
* Patients with known glucose-6-phosphate dehydrogenase deficiency (G6PD) are excluded due to an inability to administer the antidote for methemoglobinemia, methylene blue; pre-registration testing for G6PD is at the investigator's discretion and is not required for study enrollment
* Patients who are taking any medication associated with methemoglobinemia; medication must be discontinued and must have a washout period of 4 halflives or 4 weeks, whichever is shorter
* 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)
* Patients who have had a hysterectomy or are planning to have an adjuvant hysterectomy following radiation as part of their cervical cancer treatment are ineligible
* Patients scheduled to be treated with adjuvant consolidation chemotherapy at the conclusion of their standard chemoradiation

Outcome Measures

Primary Outcomes

Maximum Tolerated Dose (MTD)

The MTD was determined following a standard 3+3 design is as follows: Escalation at 0/3 DLTs, dose-reduction if \>1/3 DLT, and expansion to 6 if 1/3 DLTs. DLT is defined as the severe toxicity event that leads to the termination of the treatment as defined in section 5.5. The highest dose level where \<2/6 DLTs are observed will be declared MTD

Time frame: Up to 5 weeks

Number of Patients Who Experienced a DLT

Number of patients that experienced a DLT, evaluated using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0. DLTs are defined as the following adverse events if considered at least "possibly related" to a component of the study therapy and which occur from the start of treatment until completion of EBRT, prior to initiation of brachytherapy (i.e. the first 5 weeks if no treatments are missed): Any nausea, vomiting, diarrhea and elevation of serum creatinine level Grade 3 toxicity not resolved with maximal intervention to Grade 0-2 over 7 days (except alopecia and fatigue); Any nausea, vomiting, diarrhea and elevation of serum creatinine level Grade 4 toxicity; Any other non-hematologic toxicity ≥Grade 3; Any hematologic toxicity of ≥ Grade 4; Grade ≥3 dyspnea; Inability to deliver at least 20 of the scheduled 25 administrations of triapine at the planned dose, allowing for 2 weeks to make up missed radiation days. Inability to deliver

Time frame: Up to 5 weeks

Bioavailability of Triapine

The oral bioavailability of the oral form of the triapine will be measured as a numeric value using mass spectrophotometry.

Time frame: Up to 2 weeks

Cmax

Maximum concentration

Time frame: Up to 24 hours after dosing

Tmax

Time to maximum concentration,

Time frame: Up to 24 hours after dosing

AUC

Area Under the Concentration-Time Curve (AUC 0-last)

Time frame: Up to 24 hours after dosing

Elimination Half-life (t 1/2)

Time frame: Up to 24 hours after dosing

Secondary Outcomes

Fludeoxyglucose F18-Positron Emission Tomography Computed Tomography Metabolic Complete Response (mCR) Rate

The mCR rate at recommended phase 2 dose, defined as a metabolic complete response on PET/CT will be defined as greater than -66% reduction in tumor FDG uptake at sites of abnormal tumor FDG uptake noted on pre-treatment FDG-PET study (considering normal cardiac or liver blood pool).

Time frame: At 3 months post-treatment

Clinical Overall Response Rate

Clinical response at the recommended phase 2 dose per RECIST v1.1 Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

Time frame: 3 months post-treatment

Progression Free Survival (PFS)

Median number of months that patients survive without disease progression from end of treatment. Per RECIST v1.1, Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).

Time frame: Up to 4 years and 2 months from start of treatment

Overall Survival (OS)

Median number of months that patients remain alive after end of treatment.

Time frame: Up to 4 years and 2 months from start of treatment

Locations

University of Alabama at Birmingham Cancer Center, Birmingham, United States

Los Angeles General Medical Center, Los Angeles, United States

USC / Norris Comprehensive Cancer Center, Los Angeles, United States

Keck Medical Center of USC Pasadena, Pasadena, United States

University of Kansas Clinical Research Center, Fairway, United States

University of Kansas Cancer Center, Kansas City, United States

University of Kansas Hospital-Indian Creek Campus, Overland Park, United States

University of Kansas Hospital-Westwood Cancer Center, Westwood, United States

University of Kentucky/Markey Cancer Center, Lexington, United States

University of Michigan Comprehensive Cancer Center, Ann Arbor, United States

Wayne State University/Karmanos Cancer Institute, Detroit, United States

Weisberg Cancer Treatment Center, Farmington Hills, United States

Rutgers Cancer Institute of New Jersey, New Brunswick, United States

University of Oklahoma Health Sciences Center, Oklahoma City, United States

University of Pittsburgh Cancer Institute (UPCI), Pittsburgh, United States

University of Virginia Cancer Center, Charlottesville, United States

VCU Massey Comprehensive Cancer Center, Richmond, United States

Linked Papers

2024-12-14

Dose finding, bioavailability, and PK-PD of oral triapine with concurrent chemoradiation for locally advanced cervical cancer and vaginal cancer (ETCTN 9892)

The addition of IV triapine to chemoradiation appeared active in phase I and II studies but drug delivery is cumbersome. We examined PO triapine with cisplatin chemoradiation. We implemented a 3 + 3 design for PO triapine dose escalation with expansion, starting at 100 mg, five days a week for five weeks while receiving radiation with weekly IV cisplatin for locally advanced cervical or vaginal cancer. Maximum tolerated dose (MTD), dose limiting toxicity (DLT), adverse events, pharmacokinetics (PK), pharmacodynamics (PD), and metabolic complete response (mCR) were assessed. 19/21 patients were DLT evaluable. DLTs included grade 4 neutropenia (n = 2), leukopenia (n = 2), lymphopenia (n = 2), and hypokalemia (n = 1). Grade 3 toxicities at least possibly related were as expected for cisplatin chemoradiation: lymphopenia (n = 12), anemia (n = 10), neutropenia (n = 4), leukopenia (n = 8), decreased platelets (n = 2), hypertension (n = 1), and hyponatremia (n = 1). MTD and RP2D were established at 100 mg. 8/13 evaluable patients had a mCR. Triapine had a bioavailability of 59%. Methemoglobin levels correlated with triapine exposure. Smoking almost doubled CYP1A2 mediated triapine clearance. Oral triapine is safe when given with cisplatin chemoradiation, convenient, bioavailable. Exposure is negatively impacted by smoking, and methemoglobin is a biomarker of exposure. NCT02595879.

Linked Investigators