A Phase I Dose-escalation Study of Subcutaneous ALM201 in Patients With Advanced Ovarian Cancer and Other Solid Tumours

Study Overview
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Brief Summary
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ALM201/0001 is a Phase I, open-label, dose-escalation study of the safety, tolerability and pharmacokinetics (PK) of ALM201. Part 1 will be a dose-escalation study. Patients with advanced solid tumours will receive daily doses of ALM201 on Days 1-5, 8-12 and 15-19 in 21 day cycles. Part 2 will be a dose-expansion of the Maximum Tolerated Dose (MTD) determined in Part 1. Patients with advanced ovarian cancer will be enrolled with the main objective to determine the recommended Phase II dose.

Detailed Description
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ALM201 is a peptide with anti-angiogenic activity in a range of in-vitro and ex-vivo models. ALM201/0001 is a Phase I, multicentre, open-label, dose-escalation study of the safety, tolerability and pharmacokinetics (PK) of ALM201. The study is divided into two parts. Part 1 will enrol patients with advanced solid tumours. Patients will receive subcutaneous injection of ALM201 on Days 1-5, 8-12 and 15-19 in 21 day cycles. Patients can receive up to 8 cycles of treatment. Enrolment will follow an accelerated dose-escalation schedule until grade 2 drug-related adverse events are observed, at this point the 3+3 enrolment design will be used. There will be at least 1 week stagger between the first and subsequent patients in a new cohort dose. Dose increments will not exceed 100% escalation and will be guided by data generated from previous cycles. The dose and possibly the schedule will be adjusted to determine the Maximum Tolerated Dose (MTD). Part 2 will enrol patients with advanced ovarian cancer whose tumour has a proangiogenic profile as assessed by an angiogenesis gene signature biomarker. Patients will receive ALM201 at a dose and schedule established in Part 1. Patients will undergo safety and tumour assessments as well as blood draws for PK profiling. The safety assessments will involve physical examination, vital signs, biochemistry and haematology laboratory screens as well as immunogenicity testing. Tumour assessments will involve computed tomography (CT) or magnetic resonance imaging (MRI) scans at screening and after every 2 cycles during cycles 1 -8. Patients will be asked to provide consent for access to archived tumour tissue and for fresh biopsies to be taken at pre-dose, tumour response and/or point of disease progression for potential biomarker and pharmacodynamic assessments. PK profiling will be carried out in Cycles 1, 2, 4, 6 and 8.

Official Title
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A Phase I Open-label Multicentre Dose-escalation Study of Subcutaneous ALM201 in Patients With Advanced Ovarian Cancer and Other Solid Tumours

Conditions
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Solid Tumors, Ovarian Cancer

Intervention / Treatment
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* Drug: ALM201


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Part 1 Specific Inclusion Criterion *Patients with histologically and/or cytologically confirmed advanced solid tumour for whom no standard effective therapy is available or felt likely to be of limited efficacy and in whom a rationale for use of an anti-angiogenic treatment approach exists. Note: Previous use of anti-angiogenic therapy is allowed if tolerated Part 2 Specific Inclusion Criterion *Patients with advanced ovarian cancer, who are intolerant of or whose tumour is resistant to platinums and who have failed to respond to, or have relapsed following, standard therapy and whose tumour has a proangiogenic profile as assessed by the angiogenesis gene signature test. Note: Previous use of anti-angiogenic therapy is allowed if tolerated. General Inclusion Criteria for all Patients Measurable or evaluable disease. Recovery from previous treatment to baseline or CTCAE ≤ Grade 1, as determined by CTCAE v4.03 criteria (Appendix B), of reversible toxicities related to prior treatment, with the exception of alopecia, lymphopenia, other non-clinically significant adverse events; recovery from previous radiotherapy other than residual cutaneous effects or stable < Grade 2 gastrointestinal toxicity; complete recovery from surgery other than stable < Grade 2 toxicity. ECOG Performance Status (PS) of 0 or 1. Acceptable haematological, renal and hepatic Women must have either a negative pregnancy test prior to first study drug administration or be post menopausal. Male and female patients of childbearing potential must use appropriate methods birth control. Patients must give written informed consent and understand the requirements of the study Exclusion Criteria: For all Patients History of inability to tolerate anti-angiogenic therapies e.g. increased blood pressure (BP), proteinuria, prior thromboembolic events. Previous history of bowel obstruction, clinical evidence of gastro-intestinal obstruction, large burden of peritoneal disease or evidence of bowel involvement on computed tomography. Patents has received: any chemotherapy regimens (including investigational agents) with delayed toxicity within 4 weeks (6 weeks for prior nitrosourea or mitomycin C) of Cycle 1, Day 1, or received chemotherapy regimens given continuously or on a weekly basis which have limited potential for delayed toxicity within 2 weeks of Cycle 1, Day 1. radiotherapy, immunotherapy or biological agents (includes investigational agents) within 4 weeks of Cycle 1, Day 1. Localised palliative radiotherapy is permitted for symptom control. Documented, symptomatic or uncontrolled intracranial metastases or primary intracerebral tumours. Cancer with leptomeningeal involvement. On therapeutic anti-coagulation (aspirin dosing ≤100 mg per oral (PO) daily allowed). Previous malignancy, except for non-basal-cell carcinoma of skin or carcinoma-in-situ of the uterine cervix, unless the tumour was treated with curative intent more than 2 years prior to study entry. Active cardiac condition or history of significant cardiac condition. Known human immunodeficiency virus positivity. Active hepatitis B or C or other active liver disease (other than malignancy). Any active, clinically significant, viral, bacterial, or systemic fungal infection within 4 weeks prior to Cycle 1, Day 1. Any evidence of severe or uncontrolled systemic conditions or any other issues which make it undesirable for the patient to participate in the study or which could jeopardize compliance with the protocol.

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Solid tumours<br>Part 1 - Dose-escalation of ALM201 in patients with advanced solid tumours Daily dosing of ALM201 on Days 1-5, 8-12 and 15-19 of 21 day cycle. Escalating dose cohorts | Drug: ALM201<br>* Drug: ALM201 administered subcutaneously<br>|
| Experimental: Ovarian cancer<br>Part 2 - Dose-expansion of ALM201 Maximum Tolerated Dose (MTD) in patients with advanced ovarian cancer Daily dosing of ALM201 on Days 1-5, 8-12 and 15-19 of 21 day cycle at the MTD determined in Part 1 | Drug: ALM201<br>* Drug: ALM201 administered subcutaneously<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability - Evaluation of AEs and DLT | All events and suspected dose limiting toxicities (DLTs) were graded according to the CTCAE, version 4.03. A DLT was defined as a Grade 3 or 4 AE that, in the opinion of the CRC, was likely to be related to ALM201 and represented a clinically significant hazard to the patient. Qualifying DLT events were considered to be clinically relevant; e.g. in duration, apparent reversibility, required management, and upon consideration of the patient's medical history and/or concomitant medications. DLT events were also evaluated in terms of what was considered to be an appropriate next escalation step: In the case where the CRC agreed that an escalation step of approximately 33% or lower was merited; the toxicity of concern could be declared a DLT. In order to be evaluable for DLT assessment, a patient had to receive at least 80% of their scheduled doses (e.g. 12 of the 15), unless this lack of compliance was due to ALM201-related toxicity. | Adverse event evaluation was done during treatment and follow-up. DLT evaluation was done during cycle 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumour Response Assessment - Best Overall Response | As this was a Phase 1 study, the extent of efficacy data was expected to be limited. Using RECIST Version 1.1, a summary of clinical benefit from patients with evaluable disease was generated via CT scans: Complete Response (CR) = Disappearance of all target & non-target lesions + normalization of tumor marker; Partial Response (PR) ≥ 30% decrease in the sum of LD of target lesions; Progressive Disease (PD) ≥ 20% increase (& 5mm absolute increase) in sum of LD of target lesions or appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions; Stable Disease (SD) = Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD or persistence of one or more non-target lesion(s) or/and maintenance of tumor marker level above the normal limits. | Response assessments were done to assess clinical benefit in the efficacy population overall and at the end of cycles 2, 4 and 6, as applicable | 
| Pharmacokinetics: Tmax | Tmax was derived from the individual patient plasma concentration versus time profiles of ALM201. | Tmax was determined in cycles 1, 2, 4 and 6 of treatment | 
| Pharmacokinetics: AUC 0-t | AUC 0-t was derived from the individual patient plasma concentration versus time profiles of ALM201. | AUC 0-t was determined in cycles 1, 2, 4 and 6 of treatment | 
| Pharmacokinetics: Cmax | Cmax was derived from the individual patient plasma concentration of ALM201. | Cmax of ALM201 following subcutaneous (SC) administration of ALM201 was determined in cycles 1, 2, 4 and 6 of treatment |