Phase I-II Study to Assess the Safety, Tolerability and Efficacy of PM01183 and Atezolizumab in Patients with Advanced Small Cell Lung Cancer that Progressed Following Prior Therapy with Platinum-Based Chemotherapy

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fundacion Oncosur

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

13 Dec 2019 → ongoing

Decision date (initial)

2024-10-01

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-517705-93-00

EudraCT number

2019-001553-12

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Dose response, Therapy, Pharmacogenomic, Pharmacogenetic, Pharmacokinetic

Phase I
• To determine the maximum tolerated dose (MTD) and the recommended dose for phase II studies (RD) of PM01183 in combination with atezolizumab in advanced SCLC patients progressing after platinum doublet chemotherapy or combination of immune-chemotherapy.
Phase II
• To assess the efficacy of PM01183 in combination with atezolizumab in terms of confirmed tumor response rate according to Response Evaluation Criteria In Solid Tumors (RECIST) v.1.1 in patients with SCLC progressing after platinum doublet chemotherapy or combination of immune-chemotherapy.

Secondary objectives 11

1. Phase 1: To characterize the safety profile and feasibility of this combination.
2. Phase 1: To characterize the pharmacokinetics (PK) of PM01183 and to detect major drug-drug PK interactions.
3. Phase 1: To obtain preliminary information on the clinical antitumor activity of this combination.
4. Phase 1: In the event of DLTs being exclusively related to neutropenia, to determine the MTD and the RD of PM01183 in combination with atezolizumab in patients with advanced SCLC with compulsory primary G-CSF prophylaxis.
5. Phase 1: To evaluate pharmacogenetics (PGt) in germline DNA to identify factors that may explain individual variability in main PK parameters.
6. Phase: To evaluate pharmacogenomics (PGx) in tumor and blood samples to identify potential markers of response and/or resistance.
7. Phase 2: To confirm the safety profile and tolerability of the combination.
8. Phase 2: To further characterize the antitumor activity of the combination in terms of duration of response (DoR), clinical benefit [overall response rate (ORR) or stable disease lasting ≥3 months], progression free survival (PFS), overall survival (OS), and mid- and long-term survival (OS at 12, 18 and 24 months).
9. Phase 2: To characterize the plasma pharmacokinetics (PK) of this combination, and to detect major drug-drug PK interactions.
10. Phase 2: To evaluate pharmacogenetics (PGt) in germline DNA to identify factors that may explain individual variability in main PK parameters.
11. Phase 2: To evaluate pharmacogenomics (PGx) in tumor and blood samples to identify potential markers of response and/or resistance.

Conditions and MedDRA coding

Histologically or cytologically confirmed diagnosis of extensive or limited SCLC. Progression to first-line platinum-based chemotherapy. Measurable disease according to RECIST v.1.1.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Voluntarily signed and dated written informed consent prior to any specific study procedure.
2. Age >18 years.
3. Histologically or cytologically confirmed diagnosis of extensive or limited SCLC.
4. Progression to first-line platinum-based chemotherapy. For phase II part: Progression to first-line platinumbased chemotherapy or first-line platinum-based chemotherapy and immunotherapy (anti PD1/PDL-1). A chemotherapy and/or immunotherapy -free interval (CTFI, time from the last dose of first-line chemotherapy to the occurrence of progressive disease) ≥ 30 days.
5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) score ≤1.
6. Measurable disease according to RECIST v.1.1. Note: irradiated lesions may qualify as target if progression has been documented.
7. At least three weeks since last prior anticancer treatment (including radiotherapy) and recovery to grade ≤ 1 from any adverse event (AE) related to previous anticancer treatment (excluding sensory neuropathy, anemia, asthenia and alopecia, all grade ≤ 2) according to the National Protocol version 4.0 – 27 Feb 2023 Page 10/131 Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, v.5).
8. Adequate bone marrow, renal, hepatic, and metabolic function (assessed ≤7 days before inclusion in the study): a) Platelet count ≥100 x 109/L, hemoglobin ≥9.0 g/dL and absolute neutrophil count (ANC) ≥1.5 x 109/L. b) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3.0 x the upper limit of normal (ULN), independently of the presence of liver metastases. c) Alkaline phosphatase (AP) ≤2.5 x ULN. d) Total bilirubin ≤1.5 x ULN or direct bilirubin ≤ULN. e) International Normalized Ratio (INR) <1.5 (except if patient is on oral anticoagulation therapy). f) Calculated creatinine clearance (CrCL) ≥30 mL/minute (using Cockcroft and Gault´s formula). g) Creatine phosphokinase (CPK) ≤2.5 x ULN. h) Albumin ≥3.0 g/dL. Albumin infusion to fulfill the inclusion criterion is forbidden. i) Thyroid stimulating hormone (TSH) within institutional normal limits. If TSH is above the ULN, then a free T4 within institutional normal limits is acceptable.
9. Evidence of non-childbearing status for women of childbearing potential (WOCBP). Both women and men must agree to use a highly effective contraceptive measure during the trial, for at least five months after last atezolizumab dose, and for at least six weeks (women) or 4 months (men) after last PM01183 dose. Fertile male patients with WOCBP partners must agree to refrain from fathering a child or donating sperm during the trial and up to five months after treatment discontinuation. Acceptable methods of contraception include abstinence, intrauterine device (IUD), oral contraceptive, subdermal implant and/or double barrier.

Exclusion criteria 11

1. Active or untreated central nervous system (CNS) involvement. Treated CNS metastases have to show radiographic stability (defined as no CNS progression for at least three weeks from pre or post-radiotherapy brain scan to brain scan performed prior study entry), and patients should not have neurologic sign/symptoms secondary to the brain metastases or RT. Any steroid treatment must be completed ≥ 14 days before first dose of study treatment.
2. More than one prior chemotherapy-containing line (reProtocol version 4.0 – 27 Feb 2023 Page 11/131 challenge with the same initial regimen is not allowed).
3. Patients with radiation therapy (RT) in more than 35% of the bone marrow.
4. History of previous bone marrow and/or stem cell transplantation.
5. Impending need for RT (e.g., painful bone metastasis and/or risk of spinal cord compression).
6. History of allergy or hypersensitivity to any of the study drugs or their excipients.
7. Prior therapy with PM01183, antibodies against PD-1, PDL1, PD-L2, CD137, or cytotoxic T lymphocyte associated antigen-4 (CTLA-4). For phase II part: Prior therapy with PM01183, PD-L2, CD137, or cytotoxic T lymphocyte associated antigen-4 (CTLA-4).
8. Live vaccines within 30 days prior to start of study treatment and while on treatment.
9. History of other prior malignancy, with the exception of basal cell carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the skin, in situ cervical cancer. Patients with other prior malignancies and no disease recurrence for 3 years are eligible.
10. Concomitant diseases/conditions: a) History or presence of unstable angina, myocardial infarction, congestive heart failure defined as abnormal left ventricular ejection fraction (LVEF) < 50% assessed by multiple-gated acquisition scan (MUGA) or equivalent by ultrasound (US), or clinically significant valvular heart disease within 12 months prior first study dose. b) Symptomatic arrhythmia or any uncontrolled arrhythmia requiring ongoing treatment. c) Ongoing chronic alcohol consumption, or cirrhosis with Child-Pugh score B or C. d) Active uncontrolled infection. Serious non-healing wound, ulcer or bone fracture. e) Diagnose of immunodeficiency or receiving systemic steroids therapy (more than a daily dose of 10 mg of prednisone or equivalent per day) or any other form of immunosuppressive therapy within 14 days prior to the first study dose. f) Active autoimmune disease that required systemic treatment in the past two years (i.e., with disease-modifying agents, corticosteroids and immunosuppressive drugs). Patients with vitiligo or resolved childhood asthma/atopy are eligible, as well as patients who require intermittent use of bronchodilators or local steroid injections, patients with Protocol version 4.0 – 27 Feb 2023 Page 12/131 hypothyroidism stable on hormone replacement, patients with insulin-treated controlled type 1 diabetes or Sjogren's syndrome. g) History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis or evidence of active pneumonitis on screening chest computed tomography (CT) scans. A history of radiation pneumonitis in radiation field (fibrosis) will be allowed if asymptomatic and not requiring steroids. h) Known history of active tuberculosis (Mycobacterium tuberculosis). i) Ongoing treatment-requiring, non-neoplastic chronic liver disease of any origin. For hepatitis B, this includes positive tests for both Hepatitis B surface antigen (HBsAg) and quantitative Hepatitis B polymerase chain reaction (PCR). For hepatitis C, this includes positive tests for both Hepatitis C antibody and quantitative Hepatitis C PCR. Patients taking hepatitis-related antiviral therapy within 6 months prior to the first study dose will also be excluded. j) Known human immunodeficiency virus (HIV) infection. k) Myopathy or any clinical situation that causes significant and persistent elevation of CPK (>2.5 x ULN in two different determinations performed one week apart). l) Limitation of the patient’s ability to comply with the treatment or follow-up procedures. m) Patients who have previously experienced pericarditis, pericardial effusion and cardiac tamponade) on prior treatment with other immune-stimulatory anticancer agents. n) Any other major illness that, in the Investigator’s judgment, will substantially increase the risk associated with the patient’s participation in this study.
11. Active COVID19 infection determined by PCR (positive result of SARS-CoV-2 virus), not mandatory if fully vaccinated.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 7

1. Phase 1: Determination of MTD and RD: • The MTD will be the lowest dose level explored during dose escalation at which more than one third of evaluable patients experience a DLT during Cycle 1. • The RD will be the highest dose level explored during dose escalation at which less than one third of evaluable patients experience a DLT during Cycle 1.
2. Phase 1: If the DLTs observed with the PM01183 and atezolizumab combination without G-CSF prophylaxis are exclusively related to neutropenia, the MTD and RD will also be determined with primary G-CSF prophylaxis.
3. Phase 2: The ORR will be assessed using the RECIST v.1.1 on a set of measurable lesions identified at baseline as target lesions or as non-target lesions (if any), and followed until PD by an appropriate method [e.g., helical CT-scan, magnetic resonance imaging (MRI)], using the same method throughout the study for each individual patient.
4. Phase 2 : Adequate CNS imaging (contrast enhanced-CT or MRI, if applicable) will be performed at baseline to document any disease involvement. This assessment will not be repeated routinely unless it is clinically indicated.
5. Phase 2: Radiological tumor assessments will be performed at baseline, and every six weeks (+/- 2 weeks) until evidence of PD or start of a new antitumor therapy. If an objective response according to RECIST v.1.1 is observed, it must be confirmed by the same method at least four weeks after the date of the first documentation of response.
6. Phase 2: Clinically stable patients with suspected pseudoprogression (i.e., tumor growth from treatment effect rather than true disease progression) and perceived clinical benefit by the Investigator, might continue treatment and radiological evaluations despite RECIST-defined progression.
7. Phase 2: The date of response, the date of radiological or clinical PD, and the date of death will be registered and documented, as appropriate.

Secondary endpoints 5

1. Safety: patients will be evaluable for safety if they have received at least one partial infusion of atezolizumab and PM01183. AEs will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v.5.
2. Efficacy: antitumor activity of the combination will be evaluated in terms of: - Progression-free survival; -Duration of response (DoR); -Clinical benefit; -Overall survival (OS); -Mid- and long-term survival
3. Pharmacokinetics: PK parameters will be evaluated in plasma by standard non-compartmental methods (compartmental modeling may be performed if appropriate).
4. Pharmacogenetics: factors that may help to explain individual variability in main PK parameters, the presence or absence of germline mutations or polymorphisms that may be involved in the metabolism and/or transport of PM01183 will be analyzed in leukocyte DNA extracted.
5. Pharmacogenomics: In order to determine predictive/prognostic markers of response and/or resistance to PM01183 and atezolizumab, tumor samples available at baseline and blood samples (Day 1 of every cycle and end-of-treatment) will be evaluated in all patients. In addition, on-treatment tumor sample from biopsy (4th to 6th weeks after treatment onset) will be obtained and evaluated for patients consenting to PGx sub-study.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fundacion Oncosur

Sponsor organisation

Fundacion Oncosur

Address

Gran Via Del Marques Del Turia No 65 3 11

City

Valencia

Postcode

46004

Country

Spain

Scientific contact point

Organisation

Fundacion Oncosur

Contact name

Dr. Luis Gonzaga Paz-Ares, President of OncoSur Foudation

Public contact point

Organisation

Fundacion Oncosur

Contact name

Dr. Luis Gonzaga Paz-Ares, President of OncoSur Foudation

Third parties 1

Locations

1 EU/EEA country · 13 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 8 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications