Study of CB-103 in Adult Patients With Advanced or Metastatic Solid Tumours and Haematological Malignancies

• Sponsor: Cellestia Biotech AG
• Information provided by (Responsible Party): Cellestia Biotech AG

Study Description

Brief Summary:

This is a phase I/II, non randomized, open-label, dose escalation study to investigate the safety, tolerability and preliminary efficacy of CB-103.

Condition or disease	Intervention/treatment	Phase
Breast Cancer; Colorectal Cancer; Cholangiocellular Carcinoma; Sarcoma; Desmoid Tumour; Adenoid Cystic Carcinoma; Non-hodgkin Lymphoma; Glomus Tumor, Malignant	Drug: CB-103	Phase 1; Phase 2

Detailed Description:

This Phase I/IIA, open label, multicenter, dose escalation study of CB-103 in patients with Advanced or Metastatic Solid Tumours and Haematological Malignancies. After providing signed informed consent, patients will be screened for entry into the study. The study will be conducted in 2 stages: dose escalation in Part A of the study followed by dose expansion in Part B (Phase IIA).

Escalation cohorts will receive repeat doses of CB-103 to determine the MTD and RP2D.

CB-103 will be administered orally on a once-daily schedule, based on a 28-day treatment cycle. Aim of the expansion Phase IIA, Part B of the study will be to collect preliminary evidence of anti-tumour activity.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	165 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Phase I/IIA, Multi-Centre, Open-Label, Dose-Escalation Study With Expansion Arms to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of CB-103 Administered Orally in Adult Patients With Advanced or Metastatic Solid Tumours and Haematological Malignancies Characterised by Alterations of the NOTCH Signalling Pathway
Actual Study Start Date :	December 5, 2017
Estimated Primary Completion Date :	June 30, 2021
Estimated Study Completion Date :	June 30, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: CB-103; CB-103 capsules will be administered orally as a continuous once daily (QD) dosing during the treatment period of Part A (escalation) and Part B (expansion).	Drug: CB-103; Capsules, taken once daily during treatment period A and B. Treatment cycle is 28 days.Starting dose is 15 mg.

Outcome Measures

Primary Outcome Measures :

1. Part A: Dose limiting toxicity (DLT) [ Time Frame: 28 days ]
   Number of patients with dose limiting toxicity
2. Part B: antitumour efficacy [ Time Frame: up to 12 months ]
   Best overall response rates of each tumor type using appropriate response Evaluation Criteria

Secondary Outcome Measures :

1. Part A and B: incidence of all adverse events and serious adverse events (safety and tolerability) [ Time Frame: up to 12 months ]
   Number of participants with adverse events as a measure of safety and tolerability
2. Part A and B: pharmacokinetic - Cmax [ Time Frame: PK profiling in cycle 1 and 2 (cycle duration: 28 days) ]
   Maximum plasma concentration
3. Part A and B: pharmacokinetic - tmax [ Time Frame: PK profiling in cycle 1 and 2 (cycle duration: 28 days) ]
   Time to Cmax
4. Part A and B: pharmacokinetic - AUC [ Time Frame: PK profiling in cycle 1 and 2 (cycle duration: 28 days) ]
   Area under the curve during 8 and 24 hours
5. Part A and B: pharmacokinetic - t1/2 [ Time Frame: PK profiling in cycle 1 and 2 (cycle duration: 28 days) ]
   elimination half-life
6. Part A: preliminary antitumour efficacy [ Time Frame: up to 6 months ]
   Overall response rates of each tumor type using appropriate response evaluation criteria

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

INCLUSION CRITERIA:

1. Disease

   • Patients with histologically or cytologically confirmed solid tumours that are surgically unresectable, locally advanced, or metastatic and whose disease has progressed on at least one line of systemic therapy and for whom no standard curative therapy exists.
   • The following solid tumour indications are allowed to be enrolled into Part A of this study (dose escalation) based on known involvement of the NOTCH pathway activation in these indications: Breast cancer (triple negative breast cancer [TNBC], ER+/-, HER2+/-), gastrointestinal (GI) cancers (colorectal cancer [CRC], cholangiocellular carcinoma [CCC]), sarcomas (osteosarcoma, liposarcoma, rhabdomyosarcoma, fibrosarcoma), desmoid tumours, adenoid cystic carcinoma, and malignant glomus tumour.
   • Patients with histologically or cytologically confirmed, advanced haematological malignancies) whose disease has relapsed or progressed upon standard therapy and for whom at that point no standard therapy exists: Non-Hodgkin lymphomas (NHL): Follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma, marginal zone B cell lymphoma (MZCL), splenic marginal zone lymphoma (SMZL), mantle cell lymphoma (MCL), peripheral T-cell lymphoma (PTCL), anaplastic large cell lymphoma (ALCL).
2. Demography Men and women ≥ 18 years old on the day of signing informed consent.

3. Organ function and laboratory results

   Patients must have the following laboratory values:

   a.ANC ≥ 1.5x10^9/L (solid tumour indications) or ≥ 1.0x10^9/L (haematological malignancies) b.Haemoglobin (Hgb) ≥ 10 g/dL (≥ 100 g/L) c.Platelet count ≥ 75 x 109/L (no platelet transfusion or growth factor support in the preceding 7d) d.Total serum bilirubin ≤ 1.5xULN e.ALP ≤ 2.5xULN (if abnormalities are due to the underlying malignancy and known bone metastases, then ALP must be ≤ 5xULN) f.AST/SGOT and ALT/SGPT ≤ 2.5xULN (if abnormalities are due to the underlying malignancy and known hepatic metastases, AST and ALT must be ≤ 5xULN) g.Serum creatinine ≤ 1.5xULN (if serum creatinine > 1.5xULN, then serum creatinine clearance (CrCl) ≥ 50 mL/min h to k: Potassium, Total calcium (corrected for serum albumin), Magnesium and Phosphorus levels: within normal limits or correctable with supplements l.Serum albumin concentration ≥ 30 g/L m.Serum amylase and serum lipase ≤ ULN n.PTT ≤ 1.5 x ULN and INR ≤ 1.3 (unless receiving therapeutic anticoagulants)

4. Contraceptive measures

   • Women of childbearing potential and men must agree to use at least two highly effective forms of contraception throughout the entire clinical trial period and for 90d post-treatment completion.
   • Men whose partners could be of childbearing potential must routinely use a condom throughout the clinical trial period and for 90d posttreatment completion. The partner should also use a reliable form of contraception.
5. Signed informed consent

EXCLUSION CRITERIA

1. Medical History

   1. Patients with symptomatic CNS metastases (neurologically unstable or requiring increasing doses of steroids to control their CNS disease)
   2. Hypersensitivity to any of the excipients of CB-103
   3. Patients with unresolved nausea, vomiting, or diarrhoea of CTCAE grade > 1
   4. Impairment of GI function or presence of GI disease that may significantly alter the absorption of CB-103

   5. History of second or other primary cancer with the exception of:

      • Curatively treated non-melanomatous skin cancer
      • Curatively treated cervical cancer or breast carcinoma in situ
      • Other primary solid tumour treated with curative intent and no known active disease present and no treatment administered during the last 2 years.
2. Exclusionary concurrent medical conditions Impaired cardiac function or clinically significant cardiac diseases.

3. Prior Therapy

   • Cytotoxic chemotherapy within 3 weeks
   • Any investigational treatment (including NOTCH signaling inhibitors and prior treatment with CB-103) within 4 weeks of scheduled CB-103 dosing day 1
   • Concurrent enrolment in another therapeutic clinical trial involving ongoing therapy with any investigational or marketed product or placebo
   • Radiation therapy within 2 weeks of scheduled CB-103 dosing day 1
   • Immunotherapy, biological therapies, targeted small molecules, hormonal therapies within 3 weeks of scheduled CB-103 dosing day 1
   • Unresolved toxicity CTCAE grade > 1 from previous anti-cancer therapy or radiotherapy (excluding neurotoxicity, alopecia, ototoxicity, lymphopenia), or incomplete recovery from previous surgery.

4. Current medications

   • Drugs which prolong QT interval
   • Acid reducing agents
   • Patients receiving warfarin and phenytoin that cannot be discontinued at least one week prior to start of treatment with CB-103 and for the duration of the study
   • Anticoagulants.

5. Demography

   - Patients who are pregnant or breast feeding.

6. Others - Patients who are unable or unwilling to comply with all study requirements for clinical visits, examinations, tests, and procedures.

Contacts and Locations

Contacts

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Contact: Michael Bauer, PhD	+41 61 6332962	michael.bauer@cellestia.com

Locations

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Netherlands
Academic Medical Center	Not yet recruiting
Amsterdam, Netherlands, 1105 AZ
Maastricht UMC	Recruiting
Maastricht, Netherlands, 6202 AZ
UMC Utrecht Cancer Center	Recruiting
Utrecht, Netherlands, 3508 GA
Spain
Instituto Oncológico Baselga. IOB	Recruiting
Barcelona, Spain, 08023
Vall d'Hebron Institute of Oncology (VHIO)	Recruiting
Barcelona, Spain, 08035
Hospital Ramón y Cajal	Recruiting
Madrid, Spain, 28034
Switzerland
Oncology Institute of Southern Switzerland	Recruiting
Bellinzona, Switzerland, 6500

Sponsors and Collaborators

Cellestia Biotech AG

More Information

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Responsible Party:	Cellestia Biotech AG
ClinicalTrials.gov Identifier:	NCT03422679 History of Changes
Other Study ID Numbers:	CB103-C-101
First Posted:	February 6, 2018
Last Update Posted:	May 23, 2019
Last Verified:	May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Undecided

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Studies a U.S. FDA-regulated Drug Product:		Yes
Studies a U.S. FDA-regulated Device Product:		No
Product Manufactured in and Exported from the U.S.:		No

Keywords provided by Cellestia Biotech AG:

advanced solid tumours; haematological malignancies; phase I/II; NOTCH pathway; pan-NOTCH inhibitor

Additional relevant MeSH terms:

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Carcinoma; Neoplasms; Colorectal Neoplasms; Lymphoma, Non-Hodgkin; Carcinoma, Adenoid Cystic; Hematologic Neoplasms; Fibromatosis, Aggressive; Cholangiocarcinoma; Glomus Tumor; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site	Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Lymphoma; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Adenocarcinoma; Hematologic Diseases; Fibroma; Neoplasms, Fibrous Tissue; Neoplasms, Connective Tissue