Primary objective: to define the maximal tolerated dose (MTD) of Olaparib in combination with high dose radiotherapy with and without daily dose cisplatin in locally advanced non-small cell lung carcinoma.
Source
Brief title
Condition
- Respiratory and mediastinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
No registrations found.
Outcome measures
Primary outcome
The incidence of dose limiting toxicities (DLTs) including severe late
esophageal toxicity (sLET).
Secondary outcome
o Additional safety variables: (S)AE*s, Laboratory parameters, Vital signs,
Lung function, Long term toxicity (toxicity related to treatment, occurring or
persisting from 3 months after the last irradiation day until 5 years after
treatment)
o PK variables (AUC, Cmax, Cmin)
o Pd variables (PARP inhibition; γH2AXfoci formation)
o Objective tumor response
o Surrogate biomarkers for antitumor response: metabolic response determined by
FDG-PET/CT-imaging), change in circulating tumor cells, molecular/biological
parameters (tumor markers)
o Locoregional control rate (LRCR) at one year
o Localisation of recurrences with respect to different dose levels
administered (inside or outside Planning Target Volume)
o Progression free survival
Background summary
Concurrent chemoradiotherapy (CCRT) is the treatment of choice for patients
with locally advanced NSCLC. The cure rates however need to be improved.
Disease progression is seen in two third of patient, in part due to lack of
local control and in part due to distant metastasis.
The main mechanism by which both radiation and Cisplatin kill tumor cells is by
an accumulation of un- or misrepaired DNA damage. PARP inhibitors increase
radiation and chemotherapy (Cisplatin) response in preclinical studies
including lung cancer models. PARP inhibitors have been shown to specifically
kill homologous recombination deficient tumor cells as single agent. ATM
mutations are expected to affect DSB (Double-Strand-Breaks) repair and
homologous recombination status therefore amplifying damage induced by the
combined PARP inhibitor radiation (Cisplatin) treatment. Thus tumor targeted
treatment and radio-chemosensitization in lung cancer could be achieved in the
presence of frequently observed ATM gene mutations in lung cancer. Olaparib
exhibits low systemic toxicity profiles when given as monotherapy. When
combined with chemotherapeutic agents more toxicity is seen.
Study objective
Primary objective: to define the maximal tolerated dose (MTD) of Olaparib in
combination with high dose radiotherapy with and without daily dose cisplatin
in locally advanced non-small cell lung carcinoma.
Study design
This is an open-label, dose-escalating, non-randomized, single-centre phase I
study of olaparib combined with radiotherapy with and without daily low dose
cisplatin for locally advanced non-small cell lung cancer. Standard of care in
patients with locally advanced NSCLC is concurrent chemoradiotherapy, however
about 20% of patients receive (sequential chemo-)radiotherapy due to a too
large tumor volume in the thoracic cavity or fragility of patients. In general
toxicity observed in the concurrent chemoradiotherapy regimen is more severe
compared to radiotherapy alone or sequential chemoradiotherapy. Therefore, in
this trial dose escalation of olaparib will be done separately in patients with
and without concurrent chemotherapy. The decision to treat patients with or
without concurrent chemotherapy will be made on clinical practice.
This trial started with a classical 3+3 design with dose escalation of
olaparib. To first establish whether olaparib would not substantially raise the
risk of pneumonitis, an extra step was included in which not the olaparib dose
but the mean lung dose (MLD) was escalated (see paragraph 4.3.1). There were no
DLTs in this first dose level and there was no evidence of an increased risk of
pneumonitis. However, we did encounter more severe late esophageal toxicity
(sLET) than we expected. Therefore we decided 1) to switch to a time-to-event
continuous-reassessment-model (TITE-CRM) design to be able to include late
toxicity as DLT and 2) to add an additional target for the MTD definition, i.e.
no more than 15% of patients experiencing sLET.
In the fourth amendement this additionel target (severe late Esophagus
toxiciteit (sLET)) part of the DLT defenition. This because of chance in daily
practice at two facts: 1) new radiotherapy Esophagus dose constraint (Dmax+5 mm
= 66Gy) and at 2) All chemo-radiatie patients have daily IV hydration which
decrease the chance of having Esophagus toxicity.
TITE-CRM uses a dose level - toxicity model to identify the MTD, thereby
weighting patients according to their time of follow-up. Since in our trial the
MTD is defined by two targets (no more than 15% change on DLT AND no more than
15% change on sLET), two models will be used in each arm: a dose level - DLT
probability model and a dose-level - sLET probability model. All patients
included in an arm will be included in both the dose level-DLT and dose
level-sLET probability model of that arm. In each arm the first three patients
will be treated at the starting dose level, i.e. 25mg QD in the arm with
concurrent cisplatin and 25mg BID in the arm without concurrent cisplatin.
Thereafter, patients will be assigned to a dose level following these steps
sequentially:
1.Determine the dose level that a patient should be assigned to using the dose
level - DLT probability model (see paragraph 4.3.3)
2.Determine the dose level that a patient should be assigned to using the dose
level - sLET probability model (see paragraph 4.3.4)
3.In case of a discrepancy in the determined dose level between the dose
level-DLT probability model and the dose level-sLET probability model, pick the
lower dose level to continue with step 4.
4.Finally, apply the dose escalation restrictions (see below) to the dose level
as determined in step 3 to determine the dose level that a patient will be
assigned to.
In the fourth amendment the MTD has one target defenition (no more than15%
chance of DLT including sLET(severe late Esophagus toxicity ) Above mentioned
sequential step stappen 2 en 3 are no longer applicable.
Also the start dose level in the sequentiele (chemo-)radiation arm will be
reduced to 25 mg QD. In the CCRT arm this dose was too toxic for the above
mentioned MTD definition. In the sequentiele (chemo-)radiation arm no patienten
were yet included en the expected (esophagus) toxicity in this arm without
concurrent chemotherapy will be significant lower(Auperin, 2010, JCO)
Dose escalation restrictions:
1.A patient may not be assigned to a dose level unless at least three patients
have completed the minimal follow-up time of 3 months after end of treatment at
the dose level below. Meanwhile, a maximum of 3 more patients can be included
at the dose level below.
2.The assigned dose level may not increase more than 1 level between
consecutive patients. There is no restriction on the decrease in the number of
levels between patients.
The total DLT evaluation period for each patient is from start of treatment
until end of 1 year after end of treatment. See paragraph 4.3 for more details
on TITE-CRM.
Intervention
Patients will receive standard of care: radiotherapy alone (1), sequential
chemoradiotherapy (2) or concurrent chemoradiotherapy (3). In addition patients
will receive the experimental treatment with olaparib during the radiotherapy.
1. Radiotherapy only: Radiotherapy: A total dose of 66Gy will be given in 24
daily fractions. Overall treatment time is 5 weeks.
2. Sequential CRT: The advised chemotherapy schedules prior to the radiotherapy
are as follows:
- Cisplatin 75mg/ m2 will be given in 3hours in 1000ml NaCl 0.9% on day 1 from
each 3-weekly cycle, and after prehydration with 1000ml NaCl 0.45%/glucose 2.5%
in 12hours. Posthydration will consist of 3000ml NaCl/gluc with 500 mg/L
Magnesiumsulfaat, 20mmol/L KCl, and 2,9 ml Calcium gluconate, given in
15-24hours. The second agent will depend on the histopathology:
• In general, squamous cell carcinoma will be treated in combination with
Gemcitabine (1250mg/m2 in 500ml 0.9% NaCl on day 1 and 8). The day 8 dosage of
the last Gemcitabine, prior to the start of radiotherapy will not be given.
• In the presence of non-squamous pathology Pemetrexed (500mg/m2 in 500ml 0.9%
NaCl on day 1) is advocated as the 2nd agent. After the 2nd cycle response
assessment will take place according to RECIST criteria and the radiotherapy
plan will be designed. A total of 3-4 cycles can be given.
-Other internationally accepted schedules are 3-weekly Carboplatin (AUC6) with
Paclitaxel 200mg/m2 and 3-weekly Docetaxel (75mg/m2) with Cisplatin 75mg/m2).
- Carboplatin (AUC5) is given if contra-indications for Cisplatin are present.
Radiotherapy will start 3-4 weeks after the last cycle if disease control has
been established, depending on the schedule (in case of Gemcitabine a period of
4 weeks is being used in order to prevent excessive lung toxicity). Experienced
toxicity due to the induction chemotherapy should have resolved (in general to
CTCAE <2). A total dose of 66 Gy will be given in 24 fractions in 5 weeks.
3. Concurrent CRT:
Cisplatin: Daily dose Cisplatin 6mg/ m2 (5dys/week), 1-1.5 hr before the
irradiation (week 1 to 5), given as a 5-minutes intravenous infusion (in 50ml
NaCl 0.9%).
Radiotherapy (for all patients): A total dose of 66Gy will be given in 24
fractions from week 1 to 5.
Experimental treatment with olaparib:
Olaparib is taken orally, dependent on the dose level once daily (QD) or twice
daily (BID). The predefined dose levels are 25mg QD, 25, 50, 100, 150, 200,
300mg BID. In dose levels that Olaparib is given twice daily, Olaparib is given
for 36 consecutive days, administrated with a 12 hour interval. Olaparib will
start 2 days before start of RT and will continue for 2 days after the last RT
fraction. Olaparib is also given during the non-radiotherapy days but no
maintenance treatment is given after radiotherapy is finished. There is no
specific time interval between radiotherapy and olaparib in BID dose levels. In
dose levels that olaparib is taken once daily, olaparib will be given on all
radiotherapy days 1.5 to 2 hours before radiotherapy, excluding the weekends.
Study burden and risks
Patient will experience the side effects of the standard CCRT regimen. In
addition they may experience side effects induced by the addition of Olaparib.
These side effects are not yet known. Beside the admission for pharmacokinetics
during 1 day the participation to this trial will not require extra follow up
visits and/or physical examinations. However, for pharmacokinetics and
research purposes extra blood will be drawn (Table 9.3) as depicted in the
informed consent form, in the CCRT arm at 11 instances during the regular blood
sampling (maximum of 59 ml extra blood), in the RT alone arm at 5 instances
during the regular blood sampling and 9 instances at an additional time point.
Plesmanlaan 121
Amsterdam 1066 CX
NL
Plesmanlaan 121
Amsterdam 1066 CX
NL
Listed location countries
Age
Inclusion criteria
1. >=18 years of age
2. Histologically or cytologically confirmed diagnosis of NSCLC
3. For chemoradiotherapy patients only: stage II/III non-operable disease, without malignant pleural effusion
4. For (sequential chemo-)radiotherapy patients only: indication for radical locoregional radiotherapie
5. Acceptable pulmonary function as defined by a Fev1 of >=30% and a DLCO of >= 40% of predicted,
6. NYHA I-II functional status
7. Expected risk of radiation-induced pulmonary toxicity is modest: MLD <= 20 and maximum cord dose 50 Gy
8. WHO performance 0-1
9. Life expectancy of at least 6 months
10. Adequate hematological, renal and hepatic functions
a. Hemoglobin >= 6.2 mmol/l
b. Leucocytes > 3.0 x 109/l
c. Absolute neutrophil count > 1.5x109/l
d. Platelet count > 100 x 109/l
e. Total bilirubin < 1.5 x UNL
f. ASAT/ALAT < 2.5 x UNL
g. Alkaline phosphatase < 5 x UNL
h. Creatinine clearance >= 70 ml/min; creatinine clearance >= 50 ml/min in patients not receiving concurrent cisplatin; measured using a 24-hours urine sample or calculated using the Cockcroft-Gault formula
i. Urine dipstick for proteinuria < 2+. If urine dipstick is >= 2, 24 hour urine must demonstrate < 500 mg of protein in 24 hours
11. No pre-existing sensory neurotoxicity grade >= 2 (CTCAE)
12. Patients of reproductive potential must agree to practice two effective medically approved contraceptive method during the trial and 3 months afterwards
13. Signed written informed consent.
Exclusion criteria
1. Concurrent active malignancy other than localized, non-melanoma skin cancer or carcinoma-in-situ of the cervix (unless definitive treatment was completed 1 year or more before study entry and the patient has remained disease free)
2. Anti-cancer therapy including chemotherapy, radiotherapy, endocrine therapy, immunotherapy or use of other investigational agents within the 3 weeks prior to start of therapy (or a longer period depending on the defined characteristics of the agents used e.g. 6 weeks for mitomycin or nitrosourea). Patients may continue the use of LHRH agonists for cancer; bisphosphonates for bone disease and corticosteroids.
3. Patients, selected for sequential chemoradiotherapy, are excluded if no disease control (all responses except progression) is obtained after induction chemotherapy.
4. Prior:
o Ipsilateral radiotherapy to the chest;
o Chemotherapy within the last year
5. History of interstitial pneumonitis (to include diffuse alveolar damage, non-malignant causes of pneumonitis, ARDS, alveolitis, cryptogenic organising pneumonia, obliterative bronchiolitis, non-malignant causes of pulmonary fibrosis, eligibility based on the judgement of the primary investigator), active infection on day of enrollment
6. Significant cardiovascular disease as defined by:
o History of congestive heart failure requiring therapy;
o History of unstable angina pectoris or myocardial infarction up to 6 months prior to trial entry;
o Presence of severe valvular heart disease;
o Presence of a ventricular arrhythmia requiring treatment;
o Uncontrolled hypertension
7. Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be assessed with the patient before registration in the trial.
8. Participation in other trial with investigational drug or treatment modality
9. Co-existing serious active infection requiring parenteral antibiotics
10. Patients with hepatic disease e.g. patients with known serologically positive Hepatitis B or Hepatitis C as they may be more at risk of toxicity from Olaparib
11. Immunocompromised patients e.g. human immunodeficiency virus (HIV)
12. Myelodysplastic syndrome/acute myeloid leukaemia or features suggestive of MDS/AML on peripheral blood smear
13. Any co-existing medical condition that in the investigator*s judgement will substantially increase the risk associated with the patient*s participation in the study
14. Gastrointestinal disorders that may interfere with absorption of the study drug or patients who are not able to take oral medication
15. Concomitant medications:
a. Any previous treatment with a PARP inhibitor, including Olaparib
b. Patients receiving the following classes of inhibitors of CYP3A4 (see Section 7.4 for guidelines and wash out periods)
- Azole antifungals
- Macrolide antibiotics
- Protease inhibitors
16. Persistent grade 2 or greater toxicities, from any cause
17. Pregnant or breast-feeding women
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
Register | ID |
---|---|
EudraCT | EUCTR2011-001289-16-NL |
ClinicalTrials.gov | NCT01562210 |
CCMO | NL35195.031.11 |