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

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. III. To describe the pharmacokinetics (PK) of oral and intravenous triapine.

SECONDARY OBJECTIVES:

I. To determine whether the 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-month) is at least 70%.

II. To determine clinical overall response rate, progression-free survival, and overall survival.

III. To determine the correlation of methemoglobin proportion (%) and triapine pharmacokinetic exposure.

EXPLORATORY OBJECTIVE:

I. To determine whether active human immunodeficiency virus (HIV) antiretroviral therapy impacts the antitumor activity of triapine.

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 2 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 120 minutes on day 1 and orally (PO) on days 2-5, 8-12, 15-19, 22-26, and 29-33 within 90 minutes after pelvic irradiation, and cisplatin IV over 60-120 minutes once weekly for 5 weeks (days 2, 9, 16, 23, and 30). Treatment continues in the absence of disease progression or unacceptable toxicity. Patients may receive a 6th cycle of cisplatin IV during the parametrial boost or any make-up radiation treatment in a sixth week of external beam radiotherapy. Patients undergo the collection of blood samples on study and undergo magnetic resonance imaging (MRI) and FDG-PET/CT during follow-up.

• Biospecimen Collection (Procedure), also known as Biological Sample Collection, Biospecimen Collected, Sample Collection, Specimen Collection: Undergo collection of blood samples
• Brachytherapy (Radiation), also known as Brachytherapy, NOS, Internal Radiation, Internal Radiation Brachytherapy, Internal Radiation Therapy, Radiation Brachytherapy, Radiation, Internal: Undergo LDR brachytherapy
• Cisplatin (Drug), also known as Abiplatin, Blastolem, Briplatin, CDDP, Cis-diammine-dichloroplatinum, Cis-diamminedichloridoplatinum, Cis-diamminedichloro Platinum (II), Cis-diamminedichloroplatinum, Cis-dichloroammine Platinum (II), Cis-platinous Diamine Dichloride, Cis-platinum, Cis-platinum II, Cis-platinum II Diamine Dichloride, Cismaplat, Cisplatina, Cisplatinum, Cisplatyl, Citoplatino, Citosin, Cysplatyna, DDP, Lederplatin, Metaplatin, Neoplatin, Peyrone's Chloride, Peyrone's Salt, Placis, Plastistil, Platamine, Platiblastin, Platiblastin-S, Platinex, Platinol, Platinol- AQ, Platinol-AQ, Platinol-AQ VHA Plus, Platinoxan, Platinum, Platinum Diamminodichloride, Platiran, Platistin, Platosin: Given IV
• Computed Tomography (Procedure), also known as CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography, Computerized axial tomography (procedure), Computerized Tomography, Computerized Tomography (CT) scan, CT, CT Scan, Diagnostic CAT Scan, Diagnostic CAT Scan Service Type, tomography: Undergo FDG-PET/CT
• External Beam Radiation Therapy (Radiation), also known as Definitive Radiation Therapy, EBRT, External Beam Radiation, External Beam Radiotherapy, External Beam Radiotherapy (conventional), External Beam RT, external radiation, External Radiation Therapy, external-beam radiation, Radiation, External Beam, Teleradiotherapy, Teletherapy, Teletherapy Radiation: Undergo pelvic EBRT
• Fludeoxyglucose F-18 (Other), also known as 18FDG, FDG, Fludeoxyglucose (18F), fludeoxyglucose F 18, Fludeoxyglucose F18, Fluorine-18 2-Fluoro-2-deoxy-D-Glucose, Fluorodeoxyglucose F18: Undergo FDG-PET/CT
• High-Dose Rate Brachytherapy (Radiation), also known as Brachytherapy, High Dose, HDR, High dose brachytherapy (procedure): Undergo HDR brachytherapy
• Intensity-Modulated Radiation Therapy (Radiation), also known as IMRT, Intensity modulated radiation therapy (procedure), Intensity Modulated RT, Intensity-Modulated Radiotherapy, Radiation, Intensity-Modulated Radiotherapy: Undergo IMRT
• Magnetic Resonance Imaging (Procedure), also known as Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan, Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance, MR, MR Imaging, MRI, MRI Scan, MRIs, NMR Imaging, NMRI, Nuclear Magnetic Resonance Imaging, sMRI, Structural MRI: Undergo MRI
• Pharmacological Study (Other): Correlative studies
• Positron Emission Tomography (Procedure), also known as Medical Imaging, Positron Emission Tomography, PET, PET Scan, Positron emission tomography (procedure), Positron Emission Tomography Scan, Positron-Emission Tomography, PT: Undergo FDG-PET/CT
• Triapine (Drug), also known as 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, 3-AP, 3-Apct, OCX-0191, OCX-191, OCX191, PAN-811: Given IV and PO

Primary outcomes

• Maximum Tolerated Dose (MTD) [Up to 5 weeks]: 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
• Number of Patients Who Experienced a DLT [Up to 5 weeks]: 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
• Bioavailability of Triapine [Up to 2 weeks]: The oral bioavailability of the oral form of the triapine will be measured as a numeric value using mass spectrophotometry.
• Cmax [Up to 24 hours after dosing]: Maximum concentration
• Tmax [Up to 24 hours after dosing]: Time to maximum concentration,
• AUC [Up to 24 hours after dosing]: Area Under the Concentration-Time Curve (AUC 0-last)
• Elimination Half-life (t 1/2) [Up to 24 hours after dosing]

Secondary outcomes

• Fludeoxyglucose F18-Positron Emission Tomography Computed Tomography Metabolic Complete Response (mCR) Rate [At 3 months post-treatment]: 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).
• Clinical Overall Response Rate [3 months post-treatment]: 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.
• Progression Free Survival (PFS) [Up to 4 years and 2 months from start of treatment]: 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).
• Overall Survival (OS) [Up to 4 years and 2 months from start of treatment]: Median number of months that patients remain alive after end of treatment.

Sex: Female, ages: 18 Years to any

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

Participant flow

Outcome results

• Maximum Tolerated Dose (MTD) (Primary), Number, mg: All Participants 100
• Number of Patients Who Experienced a DLT (Primary), Count of participants, Participants: Triapine (100mg) + Chemoradiation) 1; Triapine (150mg) + Chemoradiation) 2
• Bioavailability of Triapine (Primary), Geometric mean, percentage: Triapine (100mg) + Chemoradiation) 60 (16 to 229); Triapine (150mg) + Chemoradiation) 54 (15 to 200)
• Cmax (Primary), Geometric mean, ug/L: Triapine (100mg) + Chemoradiation) 476 +/- 1.90; Triapine (150mg) + Chemoradiation) 344 +/- 1.91
• Tmax (Primary), Geometric mean, hours: Triapine (100mg) + Chemoradiation) 0.9 +/- 3.0; Triapine (150mg) + Chemoradiation) 1.5 +/- 1.5
• AUC (Primary), Geometric mean, ug/L x h: Triapine (100mg) + Chemoradiation) 990 +/- 2.09; Triapine (150mg) + Chemoradiation) 990 +/- 1.42
• Elimination Half-life (t 1/2) (Primary), Geometric mean, hours: Triapine (100mg) + Chemoradiation) 1.5 +/- 1.3; Triapine (150mg) + Chemoradiation) 1.5 +/- 1.3
• Fludeoxyglucose F18-Positron Emission Tomography Computed Tomography Metabolic Complete Response (mCR) Rate (Secondary), Number, percentage response-evaluable patients: Triapine (100mg) + Chemoradiation) 62 (30 to 86); Triapine (150mg) + Chemoradiation) 100 (32 to 100)
• Clinical Overall Response Rate (Secondary), Number, percentage response evaluable patient: Triapine (100mg) + Chemoradiation) 62 (30 to 86); Triapine (150mg) + Chemoradiation) 100 (32 to 100)
• Progression Free Survival (PFS) (Secondary), Median, months: Triapine (100mg) + Chemoradiation) NA (NA to NA); Triapine (150mg) + Chemoradiation) NA (NA to NA)
• Overall Survival (OS) (Secondary), Median, months: Triapine (100mg) + Chemoradiation) NA (NA to NA); Triapine (150mg) + Chemoradiation) NA (NA to NA)

Adverse events

Time frame: Up to 3 months post-treatment for Adverse Events Up to 4 years and 2 months for All-Cause Mortality

Serious adverse events by term

Other adverse events by term

52 more terms not shown.

• Results publication: Taylor SE, Behr S, Cooper KL, Mahdi H, Fabian D, Gallion H, Ueland F, Vargo J, Orr B, Girda E, Courtney-Brooks M, Olawaiye AB, Randall LM, Richardson DL, Sullivan SA, Huang M, Christner SM, Beriwal S, Lin Y, Chauhan A, Chu E, Kohn EC, Kunos C, Ivy SP, Beumer JH. Dose finding, bioavailability, and PK-PD of oral triapine with concurrent chemoradiation for locally advanced cervical cancer and vaginal cancer (ETCTN 9892). Cancer Chemother Pharmacol. 2024 Dec 14;95(1):4. doi: 10.1007/s00280-024-04720-1. PMID 39673591

• Study Protocol and Statistical Analysis Plan (PDF, 2023-01-12)

• Sarah E Taylor, Principal investigator, University of Pittsburgh Cancer Institute LAO

NIH grants: UM1CA186690