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

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ClinicalTrials.gov Identifier: NCT03427073
Recruitment Status : Terminated (to re-evaluate biomarker strategy for recruitment to Part 2)
First Posted : February 9, 2018
Results First Posted : September 11, 2019
Last Update Posted : September 11, 2019
Sponsor:
Information provided by (Responsible Party):
Almac Discovery

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Solid Tumors Ovarian Cancer Drug: ALM201 Phase 1

Detailed Description:

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 20 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Open-label Multicentre Dose-escalation Study of Subcutaneous ALM201 in Patients With Advanced Ovarian Cancer and Other Solid Tumours
Actual Study Start Date : April 27, 2015
Actual Primary Completion Date : March 13, 2017
Actual Study Completion Date : March 13, 2017

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Ovarian Cancer

Arm Intervention/treatment
Experimental: Solid tumours

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
Drug: ALM201 administered subcutaneously

Experimental: Ovarian cancer

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
Drug: ALM201 administered subcutaneously




Primary Outcome Measures :
  1. Safety and Tolerability - Evaluation of AEs and DLT [ Time Frame: Adverse event evaluation was done during treatment and follow-up. DLT evaluation was done during cycle 1 ]

    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.



Secondary Outcome Measures :
  1. Tumour Response Assessment - Best Overall Response [ Time Frame: 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 ]
    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.

  2. Pharmacokinetics: Tmax [ Time Frame: Tmax was determined in cycles 1, 2, 4 and 6 of treatment ]
    Tmax was derived from the individual patient plasma concentration versus time profiles of ALM201.

  3. Pharmacokinetics: AUC 0-t [ Time Frame: AUC 0-t was determined in cycles 1, 2, 4 and 6 of treatment ]
    AUC 0-t was derived from the individual patient plasma concentration versus time profiles of ALM201.

  4. Pharmacokinetics: Cmax [ Time Frame: Cmax of ALM201 following subcutaneous (SC) administration of ALM201 was determined in cycles 1, 2, 4 and 6 of treatment ]
    Cmax was derived from the individual patient plasma concentration of ALM201.



Information from the National Library of Medicine

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Ages Eligible for Study:   16 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03427073


Locations
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United Kingdom
Centre for Cancer Research and Cell Biology, Queen's University Belfast
Belfast, County Antrim, United Kingdom, BT9 7AB
Dept Medical Oncology, The Christie NHS Foundation Trust
Manchester, Lancashire, United Kingdom, M20 4BX
Freeman Hospital, Northern Centre for Cancer Care, Sir Bobby Robson Cancer Trial research Centre
Newcastle, Northumberland, United Kingdom, NE7 7DN
Sponsors and Collaborators
Almac Discovery
Investigators
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Principal Investigator: Richard Wilson, Professor Centre for Cancer Research and Cell Biology, Queen's University Belfast
  Study Documents (Full-Text)

Documents provided by Almac Discovery:
Study Protocol  [PDF] September 24, 2014
Statistical Analysis Plan  [PDF] August 1, 2017

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Responsible Party: Almac Discovery
ClinicalTrials.gov Identifier: NCT03427073    
Other Study ID Numbers: ALM201/0001
First Posted: February 9, 2018    Key Record Dates
Results First Posted: September 11, 2019
Last Update Posted: September 11, 2019
Last Verified: August 2019
Additional relevant MeSH terms:
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Ovarian Neoplasms
Carcinoma, Ovarian Epithelial
Neoplasms
Endocrine Gland Neoplasms
Neoplasms by Site
Ovarian Diseases
Adnexal Diseases
Genital Neoplasms, Female
Urogenital Neoplasms
Endocrine System Diseases
Gonadal Disorders
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type