Clinical Trials Register

Summary
EudraCT Number:	2016-001468-12
Sponsor's Protocol Code Number:	PEN-221-001
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	GB - no longer in EU/EEA
Date on which this record was first entered in the EudraCT database:	2017-01-04
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2016-001468-12

A.3

Full title of the trial

A Phase 1/2a, open-label multicenter study to assess the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of PEN-221 in patients with somatostatin receptor 2 expressing advanced cancers, including gastroenteropancreatic or lung or thymus or other neuroendocrine tumors or small cell lung cancer or large cell neuroendocrine carcinoma of the lung

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Phase 1/2a to assess PEN-221 in somatostatin receptor 2 expressing advanced cancers

A.3.2

Name or abbreviated title of the trial where available

Phase 1/2a to assess PEN-221 in somatostatin receptor 2 expressing advanced cancers

A.4.1

Sponsor's protocol code number

PEN-221-001

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02936323

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Tarveda Therapeutics, Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Tarveda Therapeutics, Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Tarveda Therapeutics, Inc.
B.5.2	Functional name of contact point	Chief Medical Officer
B.5.3	Address:
B.5.3.1	Street Address	134 Coolidge Avenue
B.5.3.2	Town/ city	Watertown
B.5.3.3	Post code	MA 02472
B.5.3.4	Country	United States
B.5.4	Telephone number	1 617 923 4100
B.5.5	Fax number	1 617 923 4101
B.5.6	E-mail	clinical.information@tarvedatx.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	PEN-221
D.3.2	Product code	PEN-221
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	N/A
D.3.9.1	CAS number	1853254-97-3
D.3.9.2	Current sponsor code	PEN-221
D.3.9.4	EV Substance Code	AS1
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2.5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Somatostatin receptor 2 (SSTR2) expressing advanced cancers, including gastroenteropancreatic (GEP) cancer or lung cancer or thymus cancer or other NETs (Neuroendocrine tumour) or small cell lung cancer (SCLC) or large cell neuroendocrine carcinoma (LCNEC) of the lung.

E.1.1.1

Medical condition in easily understood language

Pancreatic cancer, lung cancer, thymus cancer or other neuroendocrine cancers, with a specific receptor for Somatostatin

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

Phase 1 is to investigate the safety and tolerability, determine the MTD, and RP2D of PEN-221 when administered IV on an every 3 week schedule in patients with SSTR2-expressing advanced cancers, including GEP or lung or thymus or other NETs or SCLC or LCNEC of the lung.
Phase 2a is to assess the efficacy of PEN-221 as a single-agent when administered IV in patients with advanced or metastatic, well-differentiated, low or intermediate grade gastrointestinal mid-gut NETs and pancreatic NETs using CBR as defined as the proportion of patients with the best overall response of complete response, partial response, or stable disease tumour response criteria as defined by RECIST 1.1 and ORR as defined as the proportion of patients with the best overall response of complete response or partial response per RECIST 1.1 along with duration of response in patients with advanced or metastatic SCLC.

E.2.2

Secondary objectives of the trial

P1-Characterize the safety and tolerability of PEN-221 including acute and chronic toxicities and PK, DM1 and peptide from PEN-221 when given to patients with SSTR2 expressing advanced cancers per protocol, assess potential of PEN-221 to induce anti-PEN-221 in serum and assess preliminary anti-tumour activity of PEN-221 in patients with SSTR2 expressing advanced cancers per protocol using tumor response criteria as defined by RECIST 1.1, and duration of response.
P2a-Confirm MTD identified during Phase 1, further investigate safety and tolerability of RP2D and schedule of PEN-221 when given to patients with SSTR2-expressing advanced GEP NETs or SCLC. Evaluate PFS, OS safety and tolerability in the above tumour-specific patient cohorts whose tumours express SSTR2. Evaluate ORR and duration of response for gastrointestinal mid-gut NET and pancreatic NET. Characterize PK of PEN-221, DM1 and peptide from PEN-221 in above cohorts whose tumours express SSTR2.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

All patients must meet all of the following criteria to be eligible to participate:
1. Provision and understanding of signed and dated, written informed consent prior to any mandatory study-specific procedures, sampling, analysis.
2. Male or female aged ≥ 18 years.
3. ECOG PS of 0 – 1.
4. Adequate organ function within 14 days before C1D1, defined as follows:
• Bone marrow: Absolute neutrophil count (ANC) ≥ 1.5x109/L, platelet count ≥ 100x109/L, and hemoglobin ≥ 9 g/dl
• Hepatic: total bilirubin ≤ 1.5× the upper limit of normal (ULN) and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5× ULN
• Renal: If serum creatinine concentration ≥ 1.5× ULN, then estimated creatinine clearance must be ≥ 50 mL/min (Cockroft-Gault formula).
5. Serum potassium, calcium, magnesium and phosphorus within normal limits. If values are low on the initial screening assessment, supplements may be given and values repeated to confirm within normal limits.
6. If a female of childbearing potential, negative serum pregnancy test within 3 days before C1D1, or in the event of a positive serum pregnancy test, exclusion of pregnancy as assessed by transvaginal ultrasound overseen by a health care professional with experience in investigating and diagnosing early pregnancy, as human chorionic gonadotropin (HCG) can be secreted by neuroendocrine tumor. A female of childbearing potential must agree to the use of highly reliable, physician-approved contraception from 14 days before C1D1 through 3 months after the last study drug dose. Highly reliable contraception means 2 of the following: (1) established use of oral, injected, or implanted hormonal methods of contraception, (2) placement of an intrauterine device, (3) condom or occlusive cap (diaphragm or cervical vault cap with spermicidal gel, foam, film, cream, or vaginal suppository), (4) male sterilization with verified absence of sperm in ejaculate post-vasectomy. Alternatively, true abstinence is acceptable when it is the preferred and usual lifestyle of the individual. Calendar, symptothermal, post-ovulation, coitus interruptus, spermicides only, and lactational amenorrhea are not acceptable methods of contraception.
7. If male, is surgically sterile or agrees to use a condom from C1D1 through 3 months after the last study drug dose. Alternatively, true abstinence is acceptable when it is the preferred and usual lifestyle of the individual.
8. SSTR2 positive tumor as assessed using a SARI agent and as defined as follows:
• For SCLC patients, tumor uptake equal to or greater than liver uptake
• For all other patients, tumor uptake greater than liver uptake. SARI performed during the Pre-screening phase must be an agent that is approved for use by the regional regulatory authority. Documented results of SARI performed as part of a patient’s routine diagnostic assessments prior to the Pre-screening phase and within 180 days of C1D1 may be used in place of a Pre-screening phase SARI assessment.
9. Patients in Phase 1 must have a histologically- or cytologically-confirmed solid tumor in 1 of the following categories listed in the protocol after 1 or more prior lines of anticancer therapy, unless no standard treatments are available or unless such treatments are deemed not appropriate.
Anticancer therapies include liver-directed intra-arterial therapy, cytotoxic chemotherapy, everolimus, targeted inhibitors, metaiodobenzylguanidine (MIBG), and immunotherapies, but do not include somatostatin analogs.
For patients who provide written informed consent to undergo an optional tumor biopsy during the Screening phase, such patients must meet the following additional criterion before undergoing a biopsy procedure:
10. Patient must have at least 1 site of tumor that is accessible to biopsy and that is considered by the Investigator to be low risk and of sufficient size to undergo a biopsy procedure.
Patients in Phase 2a must meet the following criteria:
11. Measurable disease per RECIST 1.1 (i.e., at least 1 measurable lesion ≥ 20 mm by conventional techniques or ≥ 10 mm by spiral CT scan or MRI), with the last imaging performed within 28 days before C1D1 and documented radiographic disease progression.
12. Patients in Phase 2a must have a histologically- or cytologically-confirmed, advanced or metastatic solid tumor, in 1 of the categories listed in the protocol.

E.4

Principal exclusion criteria

Patients meeting any of the following criteria are not eligible for study participation:
1. Treatment with anticancer therapy (as defined in inclusion criterion 9) or an investigational drug or device within 3 weeks (6 weeks for mitomycin C and nitrosoureas) or 5 half-lives of the agent (whichever is shorter) before C1D1. In addition, any drug-related toxicity, with the exception of alopecia, must have recovered to ≤ Grade 1.
2. Any other malignancy known to be active or treated within 3 years of the start of screening, with the exception of treated cervical intra-epithelial neoplasia and non-melanoma skin cancer.
3. One or more of the following cardiac criteria:
• Unstable angina
• Myocardial infarction within 6 months prior to screening
• New York Heart Association Class II – IV heart failure
• Corrected QT interval (QTc) > 470 msec obtained as the mean from 3 consecutive resting ECGs using the Fredericia formula
• Clinically important abnormalities in rhythm, conduction, or morphology of resting ECG (e.g., complete left bundle branch block, third degree heart block)
• Congenital long QT syndrome
• Symptomatic orthostatic hypotension within 6 months prior to screening
• Uncontrolled hypertension.
4. Stroke or transient ischemic attack within 6 month prior to screening.
5. Grade >1 peripheral neuropathy.
6. Patient requires medication with a strong CYP3A4 inhibitor, e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole.
7. History of leptomeningeal disease or spinal cord compression.
8. Brain metastases unless asymptomatic on a stable low dose of steroids.
• Patients with SCLC or LCNEC of the lung only: CT or MRI of the brain required during screening. If positive for brain metastases, patients must have undergone radiotherapy prior to initiating treatment with PEN-221. If whole brain radiotherapy is performed, a 14-day washout is required prior to treatment with PEN-221. If stereotactic radiosurgery or stereotactic radiotherapy is performed, a 7-day washout prior to treatment with PEN-221 is required.
9. Major surgery within 28 days prior to C1D1.
10. Female who is pregnant or breast-feeding.
11. As judged by Investigator, evidence of severe or uncontrolled systemic disease, active bleeding diatheses, renal or liver transplant, or active infection including known hepatitis B, hepatitis C, or human immunodeficiency virus (HIV).
12. Hypersensitivity or history of anaphylactic reaction to octreotide or other somatostatin analogs.
13. Hypersensitivity or history of anaphylactic reaction to maytansinoids or their derivatives.
14. Any medical, psychological, or social condition that would interfere with the patient’s participation in the study.

E.5 End points

E.5.1

Primary end point(s)

E.5.1.1

Timepoint(s) of evaluation of this end point

Phase 1: The Safety Review Committee (SRC) will review the safety and tolerability of PEN-221 of each cohort to decide the next dose level to be tested. Dose escalation increments will be the decision of the SRC. Dose escalation will continue until the MTD is determined.

Phase 2a: Tumour responses as determined by RECIST 1.1 [Time Frame: Baseline, every 6 weeks (SCLC) or every 9 weeks (NET) up to time of disease progression or death (estimated 36 months)]. Duration of response (DOR) defined as the time between the date of first response (CR or PR) to the date of the first documented tumor progression (per RECIST 1.1) or death due to any cause, whichever comes first ) [Time Frame: estimated 36 months].

E.5.2

Secondary end point(s)

Phase 1 are to characterize the safety and tolerability of PEN-221, including both acute and chronic toxicities and to characterize the PK of PEN-221, DM1, and peptide from PEN-221, when administered IV in patients with SSTR2 expressing advanced cancers per protocol, assess potential of PEN-221 to induce anti-PEN-221 in serum and assess preliminary anti-tumour activity of PEN-221 in patients with SSTR2 expressing advanced cancers per protocol using tumor response criteria as defined by RECIST 1.1, and duration of response

P2a-Confirm MTD identified during Phase 1, further investigate safety and tolerability of RP2D and schedule of PEN-221 when given to patients with SSTR2-expressing advanced GEP NETs or SCLC. Evaluate PFS, OS safety and tolerability in the above tumour-specific patient cohorts whose tumours express SSTR2. Evaluate ORR and duration of response for gastrointestinal mid-gut NET and pancreatic NET. Characterize PK of PEN-221, DM1 and peptide from PEN-221 in above cohorts whose tumours express SSTR2.

E.5.2.1

Timepoint(s) of evaluation of this end point

Safety analysis: Characterize safety and tolerability of PEN-221, including acute and chronic toxicities, based on a comprehensive review of all safety data, including all observed AEs.
PK Analysis: Actual sampling times will be used for the PK analysis of the plasma concentration data for PEN-221, DM1, and peptide from PEN-221. Ph1 samples will be collected on Cycle1 Day1 and Cycle3 Day1. Ph2 samples will be collected on Cycle1 Day1 and Cycle1 Day8. PK parameters will be derived using standard non-compartmental methods.
PFS and OS: Will be determined from date of first treatment/trial entry until the date of first documented progression (PFS only) or date of death from any cause, whichever came first, assessed up to (estimated) 36 months.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Tolerability

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

Yes

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

Completion of Data entry

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1