Prospective, open-label, uncontrolled and multicenter phase I-II study in SCLC patients with ECOG PS 0-1 who have failed one prior platinum-containing line but no more than one chemotherapy-containing line. The study will be divided into two parts: a dose-ranging phase I with escalating doses of PM01183 in combination with a fixed dose of atezolizumab, followed by a single-arm phase II part with expansion at the RD determined during the phase I.
Recruiting
Phase 1
| Drug | Synonyms | Arms |
|---|---|---|
| PM 01183 | Lurbinectidin | PM01183 w/ Atezolizumab |
| Atezolizumab | Tecentriq | PM01183 w/ Atezolizumab |
Phase I Patients will receive atezolizumab at a fixed dose of 1200 mg intravenously (i.v.)
followed by PM01183 at a starting dose of 2.5 mg/m2 i.v. as a 1-hour infusion on Day 1 every
three weeks (q3wk). PM01183 doses will be escalated in successive cohorts of patients
following a modified Fibonacci scheme and a classical 3+3 design, and according to observed
tolerance and safety.
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.
| Name | Type | Description | Interventions |
|---|---|---|---|
| PM01183 w/ Atezolizumab | Experimental | Patients will receive atezolizumab at a fixed dose of 1200 mg intravenously (i.v.) as a 60-minute infusion (the second and subsequent infusions may be administered over 30 minutes) followed by PM01183 at a starting dose of 2.5 mg/m2 i.v. as a 1-hour infusion on Day 1 every three weeks (q3wk). Following analysis of cohorts, dose levels can be escalated from 2.5mg to 3.2, to a maximum dose of 3.5 mg of PM01183 |
|
Inclusion Criteria:
- Voluntarily signed and dated written informed consent prior to any specific study
procedure.
- Age >18 years.
- Histologically or cytologically confirmed diagnosis of extensive or limited SCLC.
- Progression to first-line platinum-based chemotherapy. For phase II part: a
chemotherapy-free interval (CTFI, time from the last dose of first-line chemotherapy
to the occurrence of progressive disease) ≥ 30 days.
- Available tumor tissue blocks or slides from a previous surgery or biopsy.
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) score ≤1.
- Measurable disease according to RECIST v.1.1. Note: irradiated lesions may qualify as
target if progression has been documented.
- 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 Cancer Institute Common Terminology Criteria for Adverse
Events (NCI-CTCAE, v.5).
- Adequate bone marrow, renal, hepatic, and metabolic function (assessed ≤7 days before
inclusion in the study):
- Platelet count ≥100 x 109/L, hemoglobin ≥9.0 g/dL and absolute neutrophil count (ANC)
≥1.5 x 109/L.
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3.0 x the upper
limit of normal (ULN), independently of the presence of liver metastases.
- Alkaline phosphatase (AP) ≤2.5 x ULN.
- Total bilirubin ≤1.5 x ULN or direct bilirubin ≤ULN
- International Normalized Ratio (INR) <1.5 (except if patient is on oral
anticoagulation therapy).
- Calculated creatinine clearance (CrCL) ≥30 mL/minute (using Cockcroft and Gault´s
formula).
- Creatine phosphokinase (CPK) ≤2.5 x ULN.
- Albumin ≥3.0 g/dL. Albumin infusion to fulfill the inclusion criterion is forbidden.
- Thyroid stimulating hormone (TSH) within institutional normal limits. If TSH is above
the ULN, then a free T4 within institutional normal limits is acceptable.
- 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:
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 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 (re-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, PD-L1, 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:
1. 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.
2. Symptomatic arrhythmia or any uncontrolled arrhythmia requiring ongoing
treatment.
3. Ongoing chronic alcohol consumption, or cirrhosis with Child-Pugh score B or C.
4. Active uncontrolled infection. Serious non-healing wound, ulcer or bone fracture.
5. 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.
6. 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 hypothyroidism stable on hormone replacement, patients
with insulin-treated controlled type 1 diabetes or Sjogren's syndrome.
7. 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.
8. Known history of active tuberculosis (Mycobacterium tuberculosis).
9. 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.
10. Known human immunodeficiency virus (HIV) infection.
11. 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).
12. Limitation of the patient's ability to comply with the treatment or follow-up
procedures.
13. Any other major illness that, in the Investigator's judgment, will substantially
increase the risk associated with the patient's participation in this study.
| Maximum Eligible Age: | 80 Years |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
| Measure: | Determination of Maximum Tolerable Dose |
| Time Frame: | one cycle - 21 days |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Progression-free survival |
| Time Frame: | the time from the date of registration to the date of documented progression per RECIST v.1.1 or death, assessed approximately up to 30 months |
| Safety Issue: | |
| Description: | the time from the date of registration to the date of documented progression per RECIST v.1.1 or death. If the patient receives further antitumor therapy or is lost to follow-up before PD, PFS will be censored at the date of last tumor assessment before the date of subsequent antitumor therapy. |
| Measure: | Duration of response |
| Time Frame: | from the date of first documentation of response per RECIST v.1.1 (complete or partial response, whichever comes first) to the date of documented PD or death, assessed approximately up to 30 months |
| Safety Issue: | |
| Description: | Duration of response will be calculated from the date of first documentation of response per RECIST v.1.1 (complete or partial response, whichever comes first) to the date of documented PD or death. The censoring rules defined above for PFS will be used for DoR. |
| Measure: | Clinical benefit |
| Time Frame: | ≥3 months |
| Safety Issue: | |
| Description: | defined as percentage of evaluable patient with complete response, partial response or stable disease lasting ≥3 months, as defined by RECIST v1.1. |
| Measure: | Overall survival |
| Time Frame: | from the date of registration to the date of death or last contact; approximately 30 months |
| Safety Issue: | |
| Description: | calculated from the date of registration to the date of death (death event) or last contact (in this case, survival will be censored on that date). |
| Measure: | Mid- and long-term survival |
| Time Frame: | 12, 18 and 24 months |
| Safety Issue: | |
| Description: | will be the Kaplan-Meier estimates of the probability of being alive at these time points |
| Measure: | Pharmacokinetics measures - plasma concentration |
| Time Frame: | 8 days |
| Safety Issue: | |
| Description: | PK parameters will be evaluated in plasma by standard non-compartmental methods (compartmental modeling may be performed if appropriate).The dose-exposure relationships for maximum plasma concentration (Cmax) and any potential PK interaction of atezolizumab over PM01183 will be explored. |
| Measure: | Pharmacogenetics measurements of genes implicated in the metabolism and/or transport of PM01183 |
| Time Frame: | 1 day |
| Safety Issue: | |
| Description: | In order to explore factors that may help explain individual variability in the main PK parameters, the presence or absence of germline mutations or polymorphisms in genes that may be involved in the metabolism and/or transport of PM01183 will be analyzed in leukocyte DNA extracted from one blood sample (10 mL) obtained at any time during the study, but preferably just before treatment start in Cycle 1 along with the first PK sample |
| Measure: | Pharmacogenomics measurements of predictive/prognostic markers of response and/or resistance to PM01183 and atezolizumab |
| Time Frame: | 1 day |
| Safety Issue: | |
| Description: | In order to determine predictive/prognostic markers of response and/or resistance to PM01183 and atezolizumab, tumor samples available at baseline will be evaluated in all patients. the biomarker to analize are: PD-L1 and PD-L2 expression in tumor cells and in tumor-infiltrating immune cells, presence of CD8+ T cell and CD4+ T cell in stromal-tumor edge and inside the tumor parenchyma, tumor-infiltrating lymphocyte (TIL) density, expression of granzyme B, the activated transcription factor signal transducer and activator of transcription 1 (pSTAT1), Ki67, interferon gamma (IFNƔ), tumor necrosis factor alpha (TNF-α), cytotoxic T-lymphocyte-associated protein 4 (CTLA4), fractalkine, lymphocyte-activation gene 3 (LAG-3) and T-cell immunoglobulin and mucin protein 3 (TIM-3) by IHC; and Tumor mutational burden by DNAseq with Foundation One (or another similar validated panel). |
| Measure: | Pharmacogenomics measures sub-study - tumor samples |
| Time Frame: | one sample between 4th to 6th weeks after treatment onset |
| Safety Issue: | |
| Description: | For tumor biomarkers research, tumor samples will be collected on-treatment to be analyzed at the end of the study. The on-treatment biopsy will be optional, requiring specific patient consent. The on-treatment tumor samples will be compared to baseline tumor samples and the biomarker to analize are: PD-L1 and PD-L2 expression in tumor cells and in tumor-infiltrating immune cells, presence of CD8+ T cell and CD4+ T cell in stromal-tumor edge and inside the tumor parenchyma, tumor-infiltrating lymphocyte (TIL) density, expression of granzyme B, the activated transcription factor signal transducer and activator of transcription 1 (pSTAT1), Ki67, interferon gamma (IFNƔ), tumor necrosis factor alpha (TNF-α), cytotoxic T-lymphocyte-associated protein 4 (CTLA4), fractalkine, lymphocyte-activation gene 3 (LAG-3) and T-cell immunoglobulin and mucin protein 3 (TIM-3) by IHC; and Tumor mutational burden by DNAseq with Foundation One (or another similar validated panel). |
| Measure: | Pharmacokinetics measures - area under the curve |
| Time Frame: | 8 days |
| Safety Issue: | |
| Description: | PK parameters will be evaluated in plasma by standard non-compartmental methods (compartmental modeling may be performed if appropriate).The area under the curve (AUC) will be evaluated, and any potential PK interaction of atezolizumab over PM01183 will be explored. |
| Measure: | Pharmacogenomics measures sub-study - blood samples |
| Time Frame: | First day of each cycle (each cycle is 21 days) and at the End of Treatment visit, which is up to 37 days after the last study treatment administration |
| Safety Issue: | |
| Description: | For those patients specifically consenting, blood samples for the evaluation of biomarkers will be drawn just before treatment on Day 1 of each cycle and at EOT. The biomarker to analize are: • Plasma cytokine analysis by enzyme-linked immunosorbent assay (ELISA): IFNƔ, TNF-α, interleukins IL-1β, IL-6 and IL-18, and CXCL11 (ITAC). |
| Phase: | Phase 1 |
| Primary Purpose: | Interventional |
| Overall Status: | Recruiting |
| Lead Sponsor: | Fundacion Oncosur |
March 3, 2021
