PEN-221 in Somatostatin Receptor 2 Expressing Advanced Cancers Including Neuroendocrine and Small Cell Lung Cancers

• ClinicalTrials.gov Identifier: NCT02936323
• Recruitment Status: Active, not recruiting
• First Posted: October 18, 2016
• Last Update Posted: May 22, 2020
• Sponsor: Tarveda Therapeutics
• Information provided by (Responsible Party): Tarveda Therapeutics

Study Description

Brief Summary:

Protocol PEN-221-001 is an open-label, multicenter Phase 1/2a study evaluating PEN-221 in patients with SSTR2 expressing advanced gastroenteropancreatic (GEP) or lung or thymus or other neuroendocrine tumors or small cell lung cancer or large cell neuroendocrine carcinoma of the lung.

Condition or disease	Intervention/treatment	Phase
Neuroendocrine Tumors; Carcinoma, Small Cell Lung; Neuroendocrine Carcinoma	Drug: PEN-221	Phase 1; Phase 2

Detailed Description:

Protocol PEN-221-001 will first enroll patients into a dose escalation phase, where a Bayesian logistic regression model, guided by the escalation with overdose control principle and overseen by a safety review committee, will be used to make dose recommendations and estimate the maximum tolerated dose (MTD).

Once the MTD has been confirmed, remaining patients will be enrolled into a full expansion phase to assess PEN-221 efficacy in patients with gastrointestinal mid-gut neuroendocrine tumors or pancreatic neuroendocrine tumors or small cell lung cancer.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 90 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: December 8, 2016
• Estimated Primary Completion Date: July 2020
• Estimated Study Completion Date: December 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: PEN-221; intravenous administration of PEN-221	Drug: PEN-221; Administration of PEN-221 once every three weeks

Outcome Measures

Primary Outcome Measures :

1. Phase 1: Maximum tolerated dose (MTD) and recommended Phase 2a dose (RP2D). [ Time Frame: From date of first treatment/trial entry until 28 days after last treatment, estimated 12 months ]
   Determine the MTD and the RP2D by assessing treatment related adverse events.
2. Phase 2a: Efficacy of PEN-221 in gastrointestinal mid-gut NETs and pancreatic NETs as determined by RECIST 1.1 [ Time Frame: Up to 36 months ]
   Efficacy of PEN-221 in gastrointestinal mid-gut NETs and pancreatic NETs using clinical benefit rate (CBR) defined as the best overall response of complete response (CR), partial response (PR), or stable disease (SD) according to RECIST 1.1.
3. Phase 2a: Efficacy of PEN-221 in Small Cell Lung Cancer (SCLC) as determined by RECIST 1.1 [ Time Frame: Up to 36 months ]
   Efficacy of PEN-221 in Small Cell Lung Cancer (SCLC) using objective response rate (ORR) as defined as the best overall response of CR or PR using tumor response criteria defined by RECIST 1.1, along with duration of response (DOR).

Secondary Outcome Measures :

1. Incidence of Treatment-Emergent Adverse Events (Safety and tolerability) [ Time Frame: From date of first treatment/trial entry until 28 days after last treatment, estimated 12 months ]
   Characterize the safety and tolerability of PEN-221 by assessing treatment related adverse events.
2. Maximum concentration (Cmax) of PEN-221, DM1, and peptide from the serum [ Time Frame: Up to 2 months ]
   Characterize the maximum concentration of PEN-221, DM1, and peptide in circulating blood
3. Area under the curve (AUC) of PEN-221, DM1, and peptide from the serum [ Time Frame: Up to 2 months ]
   Characterize the AUC of PEN-221, DM1, and peptide in circulating blood
4. Half-life (t1/2) of PEN-221, DM1, and peptide from the serum [ Time Frame: Up to 2 months ]
   Characterize the half-life (t1/2) of PEN-221, DM1, and peptide in circulating blood
5. Phase 1: Anti-tumor activity of PEN-221 [ Time Frame: Baseline, every 6 or 9 weeks depending on the tumor type, up to time of disease progression (per RECIST 1.1) or death (estimated 12 months) ]
   Assess the potential of preliminary anti-tumor activity of PEN-221 using tumor response criteria as defined by RECIST 1.1 and DOR.
6. Phase 2a: Maximum tolerated dose (MTD) [ Time Frame: From date of first treatment/trial entry until 28 days after last treatment, estimated 12 months ]
   Confirm the MTD identified during Phase 1 and further investigate the safety and tolerability of the recommended phase 2a dose (RP2D).
7. Phase 2a: Progression Free Survival (PFS) [ Time Frame: From date of first treatment/trial entry until first documented progression or date of death from any cause, whichever came first, assessed up to (estimated) 36 months ]
   Time from first PEN-221 dose to date of first documented disease progression per RECIST 1.1.
8. Phase 2a: Overall Survival (OS) [ Time Frame: From date of first treatment/trial entry until the date of death from any cause, assessed up to (estimated) 36 months ]
   The time from first PEN-221 dose to the date of death due to any cause.
9. Phase 2a: ORR for gastrointestinal mid-gut NETs and pancreatic NETs [ Time Frame: From the date of first treatment through the date of first documented progression, assessed up to (estimated) 36 months ]
   Evaluate ORR for gastrointestinal mid-gut NETs and pancreatic NETs.
10. Phase 2a: DOR for gastrointestinal mid-gut NETs and pancreatic NETs [ Time Frame: From the date of first treatment through the date of first documented progression, assessed up to (estimated) 36 months ]
    Evaluate DOR for gastrointestinal mid-gut NETs and pancreatic NETs.
11. Anti-PEN-221 antibodies [ Time Frame: Baseline and every 6 weeks up to end of treatment (estimated 12 months) ]
    Assess the potential of PEN-221 to induce anti-PEN-221 antibodies in the serum.

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• M/F at least 18 years old
• ECOG performance status 0 or 1
• Adequate bone marrow, liver, and kidney function within 2 weeks prior to first dose
• Serum potassium, calcium, magnesium, phosphorus within normal limits (may be supplemented)
• Adequate birth control
• Somatostatin receptor 2 positive tumor as assessed at pre-screening or within 180 d of first drug dose using indium SPECT or gallium PET

Patients in Phase 1 must have a histologically or cytologically-confirmed solid tumor in 1 of the following categories:

• Advanced small cell lung cancer (SCLC) or large cell neuroendocrine carcinoma (LCNEC) of lung progressed after at least 1 line of anticancer chemotherapy
• Advanced low or intermediate grade gastroenteropancreatic or lung or thymus neuroendocrine tumor (NET), or NET of unknown primary, progressed after at least 1 line of anticancer therapy (unless no standard treatments available or such treatments are deemed not appropriate)
• Advanced paraganglioma, pheochromocytoma, medullary thyroid carcinoma, Merkel cell carcinoma, or high grade extrapulmonary neuroendocrine carcinoma having progressed after 1 or more lines of anticancer chemotherapy (unless no standard treatments available or such treatments are deemed not appropriate)

For patients enrolling once escalation is complete (Phase 2a), disease must be measurable per RECIST 1.1 criteria with last imaging performed within 28 days prior to first drug dose

In addition to the criterion listed above, Patients in Phase 2a must have a histologically- or cytologically-confirmed, advanced or metastatic solid tumor, in 1 of the following categories: disease history specified in one of the criteria listed below:

• Well differentiated, low or intermediate grade, gastrointestinal mid-gut (arising from the lower jejunum, ileum, appendix, cecum, and proximal colon) NET with documented disease progression within 6 months prior to start of study treatment and evidence of radiographic disease progression based on scans performed not more than 15 months apart. Patients may have received 1 or more prior lines of anticancer therapy, such as somatostatin analogues, targeted agents, or liver-directed intra-arterial therapy, but are NOT eligible if they have received prior systemic cytotoxic chemotherapy.
• Well differentiated, low or intermediate grade, pancreatic NET with documented disease progression within 6 months prior to start of study treatment and evidence of radiographic disease progression based on scans performed not more than 15 months apart. Patients may have received 1 or more prior lines of anticancer therapy, such as somatostatin analogues, targeted agents, or liver-directed intra-arterial therapy, and up to 1 prior line of systemic cytotoxic chemotherapy, but are NOT eligible if they have received more than 1 prior line of systemic cytotoxic chemotherapy or if they have received prior peptide receptor radionuclide therapy (PRRT)
• SCLC after having received up to three prior lines of anticancer therapy.

Exclusion Criteria:

• Treatment with anticancer therapy or investigational drug or device within 3 wk (6 wk for nitrosureas or mitomycin C) or 5 half-lives of agent, whichever is shorter, prior to first PEN-221 drug dose, and any drug-related toxicities must have recovered to grade 1 or less
• Any other malignancy known to be active or treated within 3 years of start of screening, except cervical intra-epithelial neoplasia, superficial (non-invasive) bladder cancer, and non-melanoma skin cancer
• Cardiac criteria such as unstable angina, myocardial infarction within 6 months of screening, NY Heart Association Class 1 or 2 heart failure, QTc greater than 470 msec, congenital long Qt syndrome, symptomatic orthostatic hypotension within 6 months of screening, uncontrolled hypertension, or clinically important abnormalities in heart rhythm, conduction, morphology of resting ECG
• Stroke or transient ischemic attack within 6 months of screening
• Peripheral neuropathy greater than grade 1
• Requirement for medication with strong CYP3A4 inhibitor
• History of leptomeningeal disease or spinal cord compression
• Brain metastases unless asymptomatic on a stable low dose of steroids. Patients with SCLC or LCNEC of lung only must have CT or MRI of brain during screening, and if metastases found, must have radiotherapy with 14 day washout or stereotactic radiotherapy or radio surgery with 7 day washout prior to first drug dose.
• Major surgery within 28 days of first drug dose
• Female who is pregnant or breast feeding
• Evidence of severe uncontrolled systemic disease, bleeding diatheses, renal or liver transplant, active infection with hepatitis B or C, or HIV
• Hypersensitivity or anaphylactic reaction to any somatostatin analog or to maytansinoids

Contacts and Locations

Locations

United States, Florida

Florida Cancer Specialists South

Fort Myers, Florida, United States, 33901

Florida Cancer Specialists North

Saint Petersburg, Florida, United States, 33705

United States, Massachusetts

Massachusetts General Hospital

Boston, Massachusetts, United States, 02114

Boston Medical Center

Boston, Massachusetts, United States, 02118

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States, 02215

Dana-Farber Cancer Institute

Boston, Massachusetts, United States, 02215

United States, New York

Columbia University Medical Center/ NY Presbyterian

Manhattan, New York, United States, 10032

United States, Ohio

University Hospitals Cleveland Medical Center

Cleveland, Ohio, United States, 44106

United States, Tennessee

Sarah Cannon Research Institute/Tennessee Oncology

Nashville, Tennessee, United States, 37203

United States, Texas

MD Anderson Cancer Center

Houston, Texas, United States, 77030

United Kingdom

University College London

London, United Kingdom

The Christie NHS Trust

Manchester, United Kingdom

Southampton General Hospital

Southampton, United Kingdom

Sponsors and Collaborators

Tarveda Therapeutics

Investigators

• Study Director: Chief Medical Officer; Tarveda Therapeutics

More Information

• Responsible Party: Tarveda Therapeutics
• ClinicalTrials.gov Identifier: NCT02936323
• Other Study ID Numbers: PEN-221-001
• First Posted: October 18, 2016
• Last Update Posted: May 22, 2020
• Last Verified: February 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Tarveda Therapeutics:

SCLC small cell lung cancer; pancreatic neuroendocrine NET; GI neuroendocrine NET

Additional relevant MeSH terms:

Carcinoma; Lung Neoplasms; Small Cell Lung Carcinoma; Neuroendocrine Tumors; Carcinoma, Neuroendocrine; Carcinoma, Small Cell; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Adenocarcinoma