Phase I Study of Cantrixil in Patients With Ovarian Cancer, Fallopian Tube Cancer or Primary Peritoneal Cancer.

Phase I Study of Cantrixil in Patients With Ovarian Cancer, Fallopian Tube Cancer or Primary Peritoneal Cancer.

Phase I Study of Intra-peritoneal Cantrixil in Patients With Persistent or Recurrent Ovarian Cancer, Fallopian Tube Cancer or Primary Peritoneal Cancer.

The main purpose of this study is to determine the safety and feasibility of weekly intra-peritoneal administration of Cantrixil to women with persistent or recurrent ovarian cancer, Fallopian tube cancer or primary peritoneal cancer. The study also aims to determine the maximum tolerated dose of Cantrixil in these patients when administered as a monotherapy or a combination therapy.

This study is a progressive design with 2 discrete Parts (Part A: Dose escalation, Part B: Dose expansion. Cycle 1/Part A is a dose-finding assessment (dose escalation) to establish the MTD of Cantrixil when administered as a single dose once a week for 3 weeks. Cycle2/Part A continues with 3 additional weekly doses of Cantrixil as a monotherapy before an assessment of disease response. In Cycles 3 to 8/Part A, patients will be administered the same once weekly dose of Cantrixil they tolerated in Cycles 1 and 2 (tolerance defined as no dose limiting toxicities [DLTs] or unacceptable treatment-related adverse events [AEs]) in combination with a limited range of standard chemotherapy agent(s), in order to assess the safety and tolerability of Cantrixil in combination therapy. Standard chemotherapy drugs will be administered at the standard efficacious doses to maintain optimum benefit of known drug combinations for patients. Once the MTD has been determined in Part A, an additional 12 patients will be recruited in an expansion cohort for Part B. These patients will receive 2 cycles of Cantrixil monotherapy at the MTD, followed by up to 6 cycles of combination therapy. Patients enrolled into the respective parts of the study may not receive treatments under different parts of the protocol. To accommodate the intraperitoneal administration of Cantrixil, an in-dwelling, closed catheter or port will be inserted if the patient does not already have one. For intraperitoneal ports, the minimum period between port placement and the first administration of Cantrixil must not be shorter than 7 days. Patients should begin protocol treatment within a maximum of 28 days of enrolment (i.e., signing of consent form). Patients will start at Dose Level 0 which is calculated to be the human equivalent of 10% of the STD10 dose in rats (dose is 1/10 the severely toxic dose in 10% of rats tested). Dose levels -1 and -2 will only be activated if there are 2 DLTs at the Dose Level 0 and -1, respectively. Single patient cohorts will be treated with increasing doses of Cantrixil until an AE is observed that meets the definition of a Dose Limiting Toxicity (DLT) or, in the opinion of the Data Safety Monitoring Committee (DSMC) and the Investigator, is causally related to study treatment and warrants observing additional patients at this dose level; at this point the study will revert to a 3+3 rules based dose escalation study. Once the study enters a 3+3 rules-based design, the study will not revert back to single patient cohorts. If any unacceptable treatment-related AE or DLT is observed in any cycle, patients may be dose reduced to the next lower dose level of Cantrixil for subsequent doses of therapy. If a second unacceptable treatment-related AE or DLT is observed during any cycle within the same patient, treatment for the patient with Cantrixil will be discontinued. Investigators may continue with the standard chemotherapy at their discretion and if it is considered safe and in the patient's best interest. If any of the following unacceptable treatment-related AEs or DLTs are observed and unless clearly unrelated to study treatment (e.g., disease progression), treatment at the allocated Cantrixil dose will be discontinued and dose escalation may be considered: Hematologic toxicity Grade 4 neutropenia, lasting at least 5 days, Grade 3 or Grade 4 neutropenia associated with fever >38.5°C, Grade 4 thrombocytopenia lasting at least 5 days, Grade 3 thrombocytopenia associated with severe bleeding in the opinion of the Investigator, Dose delay of ≥3 weeks due to failure to recover counts. Any Common Terminology Criteria for Adverse Events (CTCCTCAE) version 4.03 Grade 3 or Grade 4 non haematological toxicity except: Alopecia Grade 3 abdominal pain deemed related to the port or catheter as determined by the treating physician Grade 3 anorexia Grade 3 fatigue Grade 3 nausea and/or vomiting, or diarrhoea, lasting ≤48 hours with or without maximal medical management. Grade 3 dehydration as a result of nausea and vomiting Grade 3 constipation Grade 3 metabolic abnormalities [hypokalaemia, hypomagnesemia, hypocalcaemia, hypophosphatemia]) that recovers to Grade 1 or less within 48 hours with or without medical management o• Other serious adverse events (SAEs) which, in the opinion of the treating Investigator, are related to investigational product and necessitate temporary or permanent cessation of administration o• Treatment delays of ≥3 weeks due to any treatment-related non-haematological toxicity will constitute a DLT All patients who discontinued from the study (i.e. are now Off Therapy/ End of Therapy) treatment will progress to follow-up unless the patient withdraws consent. The initiation of each new cycle of Cantrixil will be at the discretion of the Investigator and will depend on the potential or measurable benefit to the patient assuming continued tolerability and adequate organ function. Cantrixil treatment will be stopped due to RECIST version 1.1 defined disease progression observed after at least 4 cycles of therapy, recurrence of unacceptable toxicity after 1 Cantrixil dose reduction or patient consent withdrawal. Note that patients with progressive disease at the end of 2 cycles of Cantrixil monotherapy will not be taken off therapy if Cantrixil has been well tolerated. Pre-clinical data would suggest that the maximum benefit from Cantrixil will be realised as a combination therapy, hence all patients will have the opportunity to continue receiving Cantrixil as a combination therapy. Additionally, patients receiving combination therapy that are observed to have progressive disease as identified by RECIST version 1.1 criteria but who, in the opinion of the Investigator, continued to derive clinical benefit may continue Cantrixil treatment. Patients may also be discontinued from study treatment if the Investigator considers continuing therapy is not in the patient's best interest. All patients discontinued from study treatment will progress to follow-up unless the patient withdraws consent. Tumour assessment via radiological imaging will be conducted during screening and every 6 weeks after the start of therapy, i.e. at the end of monotherapy and then after every 2 cycles of combination therapy. Either contrast-enhanced magnetic resonance imaging (MRI) or contrast-enhanced computed tomography (CT) may be used, but once a modality is used at baseline this must be used consistently for that patient throughout their participation on the study. Other imaging is not mandatory, but may be performed if clinically indicated. Adverse events will be monitored for the duration of the study from the time of informed consent. Blood samples will be collected weekly for standard safety testing, or more frequently if clinically relevant, during the study. Additional volumes of blood will be collected before and after administration of Cantrixil for PK analysis (4 mL per time point as per the proposed PK schedule and for any exploratory studies (at baseline, end of Cycle 2 and end of treatment, 15 to 20 mL at each time-point).

Part A (Dose Escalation): Part A is a Dose Escalation study to determine the Maximum Tolerated Dose of Cantrixil as a monotherapy. The tolerance of Cantrixil in combination with standard chemotherapy agents will also be examined. Part B (Expansion Cohort): An expansion cohort of an additional 12 patients will be recruited at the MTD.

Cantrixil will be administered via the intraperitoneal route only. The dose of study drug that each participant will receive will depend on how far the study has progressed when the participant enrols. There are 9 potential doses of Cantrixil, they are 0.06, 0.12, 0.24 (starting dose), 0.6, 1.25, 2.5, 5, 10, or 20 mg/kg. The dose each participant receives will remain the same during the study, unless it needs to be reduced for safety reasons. The dose will not be increased. Each participant will receive the study drug once a week during the first two cycles; each cycle is 21-days (three weeks); the MTD will be determined during Cycle 1 only. If after two cycles of monotherapy, the patient tolerates Cantrixil adequately, they may continue to receive Cantrixil once a week and will also begin combination chemotherapy for another 6 cycles. Participants will receive no more than 8 cycles of study drug.

Once the MTD has been established, an expansion cohort will be recruited at the MTD. An additional 12 patients will be recruited in this cohort on top of those recruited in Part A at the MTD. These patients will be subjected to the same intervention described in Part A with 2 cycles of monotherapy followed by up to 6 cycles of combination therapy.

Determination of the MTD of Cantrixil using standard safety monitoring assessments when administered as a monotherapy.

Description of the PK of Cantrixil when administered as a monotherapy and in combination with standard chemotherapy agent(s)

TTP will be measured as the time from treatment start until objective tumour disease progression as defined by RECIST version 1.1 and/or GCIG criteria, but does not include deaths.

The time to paracentesis will be measured as the time from treatment initiation until the next paracentesis event for ascites.

The volume of abdominal fluid will be measured by estimating the volume of malignant ascites drained at each paracentesis event.

Disease response will be measured using RECIST version 1.1 criteria; during Follow-up, response may be also assessed using the Gynecological Cancer Intergroup (GCIG) response criteria that incorporates CA-125 measurements

Concentration of CA-125 in peripheral blood will be assayed in local laboratories using locally validated assays at baseline and then weekly during treatment, at the End of Therapy and during Follow-up.

Determination of the optimum dose and administration schedule (i.e. weekly vs twice weekly administration) using standard safety monitoring assessments, PK measurements and tolerability of delivery in the study centre.

Enumeration of CETC in peripheral blood and malignant ascites (if present) will be assayed using the MAINTRAC® CETC Count method by Genostics or similar methodology.

Clonogenicity of CETCs in peripheral blood and malignant ascites (if present) will be measured using the MAINTRAC® Tumour Sphere Units assay by Genostics or similar methodology.

Expression of stem cell markers CD44 and ALDH1 in the isolated colonies will be measured using fluorescein isothiocyanate-labelled (FITC-labelled) or alternatively labelled antibodies and scanning fluorescent microscopy techniques.

Inclusion Criteria: Patients must have recurrent or persistent epithelial ovarian, fallopian tube, or primary peritoneal cancer. The original diagnosis must be verified by a histology report. All histological sub-types and all grades of disease are eligible to participate; grade, histological sub-type and breast cancer susceptibility gene (BRCA) status must be recorded at study entry. Patients must be female and at least 18 years old. Patients with malignant ascites are eligible to participate; paracentesis will be conducted before the administration of Cantrixil. Drainage of the maximum volume of ascites necessary for symptomatic relief should be performed according to local standard operating procedures before administration of Cantrixil. Patients must have completed at least two (2) or more prior therapies (including adjuvant therapy) for their ovarian, Fallopian tube or primary peritoneal cancer prior to participation in the current study; all prior therapies must be recorded at baseline. Patients that have received prior intraperitoneal therapy are eligible for this study. Patients must have platinum-resistant relapsed disease, platinum refractory disease, or have documented intolerance to platinum therapy. Patients will not be eligible based on rising CA-125 levels alone, patients must have other clinical symptoms (such as malignant ascites) or radiological tumour measurements that support disease recurrence or progression. At least 4 weeks must have passed from any previous therapy and any toxicities from prior therapies (6 weeks for bevacizumab, nitrosoureas or mitomycin C treatment) must have resolved to less than or equal to Common Terminology Criteria for Adverse Events (CTCAE version 4.03) Grade 1 with the exception of alopecia, Grade 2 prior platinum-therapy related neuropathy and Grade 2 anaemia. Patients must have a performance status of Eastern Cooperative Oncology Group (ECOG) 0 to 2 and, in the Investigator's opinion, be able to complete at least a major part of the study. Patients must be willing and able to undergo insertion of a port or catheter for intraperitoneal access; the type of port or catheter used will be recorded. Patients may have measurable or non-measurable disease; disease response and progression will be measured and assessed according to RECIST version 1.1 criteria using contrast CT, MRI and CA 125 measurements. Patients must have acceptable hepatic and marrow function as defined below: Absolute neutrophil count >1.5 x 109/L Platelets >100 x 109/L Total bilirubin; <2.5 times the institutional upper limit of normal (ULN) Haemoglobin (Hb) of >10 g/dL; patients with Hb >9g/dL will be considered for this study if they have not received a transfusion or other bone marrow support. Patients with Hb >10 g/dL that have received a recent transfusion will only be eligible if there has been a wash-out period of 7 days for rhesus factor and 10 days for platelet transfusions, respectively. Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/ alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]) ≤2.5 x institutional ULN. Serum creatinine <1.5 x ULN Prothrombin time (PT) or international normalised ratio (INR) ≤1.5 x ULN and activated partial thromboplastin time (aPTT) ≤1.5 x ULN if not on anticoagulation treatments. Patients must be willing and able to comply with all study requirements, including treatment timing and/or nature of required assessments and treatment at designated study centre. Each participant must be adequately informed about the purpose of the study; potential benefits and risks; their right to refuse participation or to withdraw consent at any time; institutional affiliation and potential competing interests of the researcher; and sources of study funding and have signed and dated a written informed consent form. Exclusion Criteria: Patients who have had chemotherapy, biologic therapy, immunotherapy, or radiotherapy within 4 weeks (6 weeks for bevacizumab, nitrosoureas or mitomycin C) prior to entering the study. Patients must not have had major surgery within 4 weeks prior to screening. Patients may not have received any other investigational medicinal products (IMPs) or participated in any other interventional clinical research studies within 3 months of the first Cantrixil administration. Patients receiving any medications or substances that are strong inhibitors or inducers of cytochrome P450 (CYP)1A2, CYP2B6 and CYP3A4 or those substances with narrow therapeutic index are not to be enrolled. These compounds are prohibited from screening until completion of end of therapy or first post-treatment follow-up visit. For a list of prohibited medications see the University of Indiana Clinical Pharmacology Department's P450 Drug Interaction Table (http://medicine.iupui.edu/clinpharm/ddis/main-table/). Note: the use of paclitaxel is allowed, but only 24 hours after Cantrixil administration. Patients at high risk of bowel perforation are excluded, including but not limited to any one or more of the following; Patients with a recent history (previous 12 months) of bowel obstruction prior to study entry Patients with CT scans that suggest invasion of bowel by tumour Patients with symptoms to suggest impending bowel obstruction Patients with prior whole abdominal radiotherapy Patients with chronic inflammatory bowel diseases such as Crohn's disease or ulcerative colitis Patients may not have uncontrolled or severe systemic diseases or psychiatric conditions, which in the treating physician's opinion makes it unsafe for the patient to participate in the study or would hinder compliance with the protocol. Screening for chronic conditions is not required. Patients that are pregnant, lactating, or unable to adopt adequate contraception are excluded. Women of childbearing potential must have a negative pregnancy test within 7 days prior to screening. Patients with a known history of hepatitis B or C. Patients known to have tested positive for human immunodeficiency virus (HIV) Patients with a known hypersensitivity to or serious reaction to benzopyrans are excluded.