Presentation is loading. Please wait.

Presentation is loading. Please wait.

Clinical trials challenges with targeted agents Paolo Bruzzi Clinical Epidemiology, Dept. of Epidemiology and Prevention, Istituto Nazionale per la Ricerca.

Similar presentations


Presentation on theme: "Clinical trials challenges with targeted agents Paolo Bruzzi Clinical Epidemiology, Dept. of Epidemiology and Prevention, Istituto Nazionale per la Ricerca."— Presentation transcript:

1 Clinical trials challenges with targeted agents Paolo Bruzzi Clinical Epidemiology, Dept. of Epidemiology and Prevention, Istituto Nazionale per la Ricerca sul Cancro Genoa - Italy Rome, 28/3/2008

2 Trials: Rationale of Phases 1.Any new drug, when first used in man, involves unknown risks, and has unknown pharmacological and toxic properties: PHASE I

3 Aims of of clinical trials Phase I Question: (How much, often, etc.) can (should) I use the drug?

4 Aims of of clinical trials Phase I Question: How (much, often, etc.) can (should) I use the drug? Endpoints: Toxicity, Pharmacology MTD (Dose-response?)

5 Rationale of Phases 1.Any new drug, when first used in man, involves unknown risks, and has unknown pharmacological and toxic properties : PHASE I 2.Before starting a long and expensive efficacy trial, it is convenient to know if the drug has the effects (ACTIVITY) that make its efficacy plausible: PHASE II

6 Activity vs Efficacy Efficacy: The benefit desired by the patient Usually, quantity and/or quality of life

7 Activity vs Efficacy Efficacy: The benefit desired by the patient Activity: The direct effects (mechanisms) by which the treatment is supposed to produce the benefit

8 Activity vs Efficacy Efficacy: The benefit desired by the patient Activity: –Antihypertensive –Diuretic –Lipid Lowering –Antibacterial –Antiarythmic

9 Aims of of clinical trials Phase I Phase II Question: Does the drug what it is supposed to do to the disease (the organism)?

10 Aims of of clinical trials Phase I Phase II Question: Does the drug what it is supposed to do to the disease (the organism)? Endpoints: Activity Endpoints (Changes in the disease or in physiopathological parameters)

11 Rationale of Phases 1.Any new drug, when first used in man, involves unknown risks, and has unknown pharmacological and toxic properties : PHASE I 2.Before starting a long and expensive efficacy trial, it is necessary to know if the drug has the effects (ACTIVITY) that make its efficacy plausible : PHASE II 3.The EFFICACY of a treatment is not warranted by its Activity: PHASE III

12 Activity = Mechanisms of action

13

14 Aims of of clinical trials Phase I Phase II Phase III Question: Does the drug do what the patient expects from it?

15 Aims of of clinical trials Phase I Phase II Phase III Question: Does the drug do what the patient expects from it? Endpoints: Efficacy Endpoint(s) Overall Survival - QoL Surrogate endpoints

16 Note The rationale of trial phases has no implications for their methodology The methodology of phases is related to: –Therapeutic paradigm –Characteristics of experimental therapy –Endpoints –Ethical Problems

17 Trials of Cytotoxic Drugs Underlying Paradigm 1.Monotonic dose-effect relationship (the more the better)

18 Trials of Cytotoxic Drugs Underlying Paradigm 1.Monotonic dose-effect relationship 2.Direct cell killing

19 Trials of Cytotoxic Drugs Underlying Paradigm 1.Monotonic dose-effect relationship 2.Direct cell killing 3.Constant proportion of tumor cells killed (independent of the number of cells)

20 Consequences PHASE I trials: Aim: (The more the better ->) Finding the Maximum Tolerated Dose (MTD) of the drug (combination) Note: MTD? (single dose, total dose, dose- intensity, dose-density, mode of injection, etc.)

21 Consequences PHASE I trials: Toxicity: Specific Uncontrolled phase I trials

22 Consequences PHASE II trials: Aim: (Direct cell killing ->) Assessing the antitumor activity (ability to differentially kill tumor cells) Antitumor activity: Reduction of volume of tumor mass Primary= Objective Response (%)

23 Phase II: Implications Spontaneous tumor reduction (>50%) is rare (<1%)  No need for control groups

24 Phase II: Implications Uncontrolled Phase II trials

25 Phase II: Implications Uncontrolled Phase II trials Need to assess tumor reduction –Patients with measurable lesions –Unresectable cancers –(Preoperative (primary) chemotherapy)

26 Phase II: Implications Uncontrolled Phase II trials Phase II trials in metastatic pts

27 Phase II: Implications Uncontrolled Phase II trials Phase II trials in metastatic pts Proportional reduction: Effects in metastatic cancer  Micrometastatic disease

28 Phase II: Implications Uncontrolled Phase II trials Phase II trials in metastatic pts Phase III trials in disease-free (and metastatic) patients

29 Development of cytotoxic drugs Phase I: Uncontrolled, dose-escalation in heavily pretreated pts Phase II: Uncontrolled, response rate with MTD in pts with measurable disease Phase III: Large RCT‘s, OS (RFS/PFS) in unselected, resected/metastatic pts

30 Development of cytotoxic drugs Other peculiarities of phase III trials Unselected patients –Site- and stage-specific

31 Development of cytotoxic drugs Other peculiarities of phase III trials Unselected patients –Site- and stage-specific –Histology-specific? (e.g. NSCLC)

32 Development of cytotoxic drugs Other peculiarities of phase III trials Unselected patients Pragmatic (EFFECTIVENESS)

33 Development of cytotoxic drugs Other peculiarities of phase III trials Unselected patients Pragmatic (EFFECTIVENESS) Classical ‘Frequentist’ Statistics –Test of significance, power –Adjustment of p values for multiple looks –Frequentist 95% CI

34 Development of a new cytotoxic drug

35 ‘New’ Anticancer Therapies Targeted Therapies Biological Response Modifiers (e.g.IL-2) Cancer Vaccines Cell Therapy Gene Therapy Anti-angiogenetic drugs Others Associations?

36 Targeted therapies Definition (NCI Dictionary) targeted therapy (...THAYR-uh-pee) A type of treatment that uses drugs or other substances, such as monoclonal antibodies, to identify and attack specific cancer cells without harming normal cells.

37 Targeted therapies G. Sledge (JCO, 2005): ‘‘A targeted therapy should attack a biologically important process (usually, though not necessarily, a single molecule), preferably one central to a hallmark of cancer. The target should be measurable in the clinic, and measurement of the target (in either quantitative or qualitative terms) should correlate with clinical outcome when the targeted therapy is administered’’.

38 Targeted therapies Working definition: Drugs aimed at specific (functional) targets of (some) cancer cells

39 Targeted therapies Working definition: Drugs aimed at specific targets of (some) cancer cell 1° example: Tamoxifen  Estrogen receptors in breast cancer cells

40 Recent examples (Targets) Epidermal Growth Factor Receptor (Anti-EGFR) Vascular Endothelial Growth factor (anti-VEGF) Human epidermal growth factor receptor (anti-HER2) Protein products of oncogenes (e.g. BRC/Abl) Multitargeted agents Other pathways/receptors

41 Recent examples (drugs) Monoclonal Antibodies (xxxx…ab) Tyrosine kinase inhibitors (xxx…ib) Other Inhibitors (mTOR, FTI,etc) (xxxx….ib) Others

42 Recent examples Epidermal Growth Factor Receptor (Anti-EGFR) Vascular Endothelial Growth factor (anti-VEGF) Human epidermal growth factor receptor (anti-HER2) Protein products of oncogenes (e.g. BRC/Abl) Multitargeted agents Other pathways/receptors Monoclonal Antibodies (xxxx…ab) Tyrosine kinase inhibitors (xxx…ib) Other inhibitors (xxxx….ib) Others

43 Common Issues Low toxicity? (interactions with CTX?)

44 Common Issues Low toxicity (interactions with CTX?) Direct cell killing?  Reduction in tumor size?  Objective Response plausible? Marginal effects

45 Common Issues Low toxicity (interactions with CTX?) Moderate/low anticancer activity (response rate)

46 Common Issues Low toxicity (interactions with CTX?) Moderate/low anticancer activity (response rate) Dose-Response? Often Unlikely

47 Common Issues Low toxicity (interactions with CTX?) Moderate/low anticancer activity (response rate) Dose-Response? Often Unlikely Transient effect –Treatment duration –Resistance (partial, reversible)

48 Common Issues Low toxicity (interactions with CTX?) Moderate/low anticancer activity (response rate) Dose-Response? Often Unlikely Transient effect Effect only in the presence of the target?

49 Common Issues Low toxicity (interactions with CTX?) Moderate/low anticancer activity (response rate) Dose-Response? Often Unlikely Transient effect Effect only in the presence of the target? Positive interaction with CTX/RTX?

50 Common Issues Low toxicity (interactions with CTX?) Moderate/low anticancer activity (response rate) Dose-Response? Often Unlikely Transient effect Effect only in the presence of the target? Positive interaction with CTX/RTX? Activity independent of tumor size? (Yes?)

51 Consequences Trials of novel therapies Phase I: Dose? Phase II: Activity? Phase III: Effectiveness? New Methodology

52 Phase I trials of targeted therapies MTD-Optimal Dose -Lowest effective Dose? Safety Dose-toxicity Pharmacokinetics (e.g. saturation) (MTD)? Biologically Effective Dose (Biologic endpoints from animal/human models) Dose/Activity (Phase I-II)

53 Phase I-II trials of targeted therapies Study design (for dose-activity) Larger size Randomization? (e.g. different doses) Patients? Duration of treatment? Single agent or + CTX? Endpoint?

54 Phase II (or I-II) trials Main Challenge How to assess the activity of novel therapies? Design and conduct of phase II studies of targeted anticancer therapy: Recommendations from the task force on methodology for the development of innovative cancer therapies (MDICT) - Boot et al, Eur J Cancer 2007

55 Approach used in the development of some novel anticancer therapies Phase IA: Safety, Toxicity Biological Marker ? Phase III: Efficacy

56 Phase II (or I-II) trials Reasons for phase II trials (Simon, JCO 2001): Economy: Insufficient resources to test all drugs in all tumor types by phase III trials

57 Phase II (or I-II) trials Reasons for phase II trials (Simon, JCO 2001): Economy Ethics: inappropriate to expose large numbers of pts in a phase III trial to an agent with no demonstrated activity.

58 Phase II (or I-II) trials Reasons for phase II trials (Simon, JCO 2001): Economy Ethics Opportunity: chance to modify dose of the agent or to better select the target population for the phase III trials

59 Phase II (or I-II) trials Reasons for phase II trials (Simon, JCO 2001): Economy Ethics Opportunity Science, i.e. statistics: Results of subsequent phase III trial –Positive: More convincing –Negative: Can be interpreted

60 Phase II (or I-II) trials of targeted therapies 1.Endpoint 2.Design 3.Selection of patients

61 Phase II (or I-II) trials Activity Endpoint DesignSelection of pts

62 a) Endpoints of Phase II (or I-II) trials Activity endpoints vs Surrogate endpoints

63 Endpoints in phase II trials Activity Endpoints: Assess mechanisms, direct effects on the disease/organism

64 Endpoints in phase II trials Activity Endpoints: Surrogate endpoints: Intermediate events/markers/ parameters that (are assumed to) reflect the effects of the treatment on the true endpoint

65 Endpoints Surrogate endpoints Activity Endpoints

66 Activity endpoints may not be valid surrogate’ endpoints Antiarythmic drugs –Effects on arythmia  Effects on sudden deaths Cast trial: active antiarythmic drugs increased SD mortality

67 Activity endpoints may not be valid surrogate’ endpoints Screening tests –Earlier diagnosis  Reduction in mortality? Mayo clinic lung project: earlier diagnosis but no decrease in mortality

68 Activity endpoints may not be valid surrogate’ endpoints (Chemo)prevention –Incidence  Mortality? Tamoxifen in BC ?

69 Plausible surrogate endpoints may not be activity endpoints EndpointSurrogateActivity Obj. response yes ? For cytotoxic drugs RFSyes ?No PFSyes ?No

70 Endpoints in phase II trials Phase II trials, if possible, should use Activity endpoints –Stronger rationale for phase III trials –Smaller size –Negative Phase III can be interpreted

71 Endpoints in phase II trials Phase II trials, if possible, should use Activity endpoints If not possible, plausible (validated?) surrogate endpoints are acceptable

72 Endpoints in Phase II (I-II) trials 1.Biological Activity Tumor tissue markers, circ. tum. cells, plasma/serum markers, metabolic imaging, etc.

73 Endpoints in Phase II (I-II) trials 1.Biological Example: The smallest dose that inhibited the phosphorylation of CRKL, an adapter protein that is a major substrate of the deregulated BCR/ABL tyrosine kinase and is aberrantly tyrosine-phosphorylated in chromosome Philadelphia-positive leukemia cells, was 400 mg. (Rosa DD et al., Molecular-targeted therapies: Lessons from..., Cancer Treat Rev (2007), doi: /j.ctrv )

74 Endpoints in Phase II (I-II) trials 1.Biological Example: Results from a phase I study evaluating cetuximab in patients with advanced solid tumours expressing EGFR showed that it effectively abrogated EGFR-mediated cell signalling, with no alteration in total EGFR protein. (Rosa DD et al., Molecular-targeted therapies: Lessons from..., Cancer Treat Rev (2007), doi: /j.ctrv )

75 Biological endpoints -Sensitivity and Specificity of the Endpoint -Sensitive: Representative of the mode of action of the treatment -Specific: Does not show spontaneous modifications

76 Biological Endpoints Specific Target -Eligibility restricted -Stronger effect (Smaller sample size) -More convincing evidence

77 Biological Endpoints Specific Target Not specific (e.g. TLI) -Weaker effect (large sample size) -Need for a randomised control group -Less convincing evidence

78 Biological Endpoints -Sensitivity and Specificity of the Endpoint? (preclin. studies, studies in other cancers, with similar treatments) Wrong endpoint  effective treatment discarded

79 Biological Endpoints -Sensitivity and Specificity of the Endpoint? -Eligible patients -Measurable target -Patients amenable to multiple biopsies -Organizational and clinical burden

80 Biological Endpoints -Sensitivity and Specificity of the Endpoint? -Eligible patients -Sufficient evidence to start a phase III trial?

81 Endpoints in Phase II (I-II) trials 2. Clinical (surrogate) Endpoints

82 Endpoints in Phase II (I-II) trials 2. Clinical (surrogate) Endpoints Objective response –Plausible? –Specific (>50% reduction in tumor mass within few months) –Sensitive? If not observed, the treatment can be discarded as inactive?

83 Endpoints in Phase II (I-II) trials 2. Clinical (surrogate) Endpoints Objective response Time to progression/relapse (median TTP, % Progression- free at 6 months, etc.)

84 Endpoints in Phase II (I-II) trials 2. Clinical (surrogate) Endpoints Objective response Time to progression/relapse –Historical data unreliable (control group?) –Randomised? –2 stage designs? –Sample Size? (close to phase III trials)

85 Time to Progression/Relapse Surrogate endpoint! If a relevant effect on TTP is seen in a phase II trial, is the randomised Phase III trial still ethical?

86 Endpoints in Phase II (I-II) trials 2. Clinical Endpoints Objective response Time to progression/relapse Clinical Benefit (QoL, improvement in symtoms, combined endpoints) –Validated? –Same problems of TTP

87 b) Designs in Phase II (I-II) trials 1.Single-arm designs Absolute values (e.g. 50% resp. Rate) Relative to Historical Controls Before-after designs –Regression to the mean? –Natural history of the tumor? –Bias?

88 Designs in Phase II (I-II) trials 1.Single-arm designs: Can be used if a) The endpoint is very specific or b) Historical data are very solid and stable and c) The endpoint can be assessed objectively/unbiasedly

89 Designs in Phase II (I-II) trials 1.Single-arm designs 2.Non-comparative randomised trials Used to select the most active drug(s) among a series of drugs/combinations Problems in the interpretation of results Seldom used with novel therapies

90 Designs in Phase II (I-II) trials 1.Single-arm designs 2.Non-comparative randomised trials 3.Randomised comparative Phase II trials Necessary for non specific endpoints Sample Size < than in Phase III trials Various designs (e.g. random discontinuation)

91 Randomised Phase II (I-II) trials Control arm Untreated ? –Responding/Stable pts after standard therapy –Patients not candidate to further therapies –To encourage pts to participate If endpoint is TTP, cross-over after progression If biological endpoint, cross over after its assessment

92 Randomised Phase II (I-II) trials Control arm Untreated ? Standard (chemo)therapy? –Same chemotherapy also in exp. arm –Negative/positive interactions?

93 Randomised Phase II (I-II) trials Reduced Sample Size Large Effect (esp. for biological endpoints) Relaxed significance level –0.10 (-23%) –0.20 (- 47%) Stopping rules for evidence of futility (clearly inactive treatment)

94 c) Selection of patients for Phase II trials –Bearing the (presumed) target Increased power

95 Trial in Unselected patients - Response rate from 20% to 40% (in pts with the target)  =0.05  =0-2

96 Target? Not always a yes/no phenomenon (e.g. number of copies of HER2) Reliability of assessement (technique, inter- intra-laboratory variability) Necessary but not sufficient (e.g. EGFR and K- ras mutation) Sufficient but not necessary (e.g. multitargeted agents)

97 c) Selection of patients for Phase II trials –Bearing the (presumed) target Increased power Only if strong biologic rationale Risk if wrong target

98 Phase II (I-II) trials Selection of patients –With the (presumed) target –All patients Identification a posteriori of markers of susceptibility (targets) Much larger sample size (if true target)

99 Unselected patients 182 pts 300 pts 600 pts 900 pts

100 Phase II (I-II) trials Selection of patients –With the (presumed) target –All patients –‘Enriched’ populations (unbalanced sampling of pts with the target)

101 ‘Enriched’ populations 182 pts 300 pts 600 pts 900 pts pts: 50% with the mutation

102 Efficacy Trials of Novel Therapies Standard RCT’s – Overall Survival (or surrogates) Peculiarities –Selected patients (target present) –Organizational burden –Costs –Long-term toxicity –(smaller size/larger effect)?

103 Development of a ‘novel’ therapy Strong preclinical evidence of activity on the target

104 Development of a ‘novel’ therapy Strong preclinical evidence of activity Phase IA: Safety

105 Development of a ‘novel’ therapy Strong preclinical evidence of activity Phase IA: Safety Phase I-II Dose-response Randomised Comparison Biological endopint Stop if no activity – Unselected pts

106 Development of a ‘novel’ therapy Strong preclinical evidence of activity Phase IA: Safety Phase I-II Dose-response Randomised Comparison Biological endopint Stop if no activity – Unselected pts Phase IIB Surrogate endpoint (sel. Pts?)

107 Development of a ‘novel’ therapy Strong preclinical evidence of activity Phase IA: Safety Phase I-II Dose-response Randomised Comparison Biological endopint Stop if no activity – Unselected pts Phase IIB Surrogate endpoint (sel. Pts) Efficacy (OS, PFS, RFS)

108 Development of a ‘novel’ therapy Strong preclinical evidence of activity Phase IA: Safety Phase I-II Dose-response Randomised Comparison Biological endopint Stop if no activity – Unselected pts Phase IIB Surrogate endpoint (sel. Pts) Stop if no difference with control arm (futility) or toxicity Efficacy (OS, PFS, RFS)

109 Development of a ‘novel’ therapy Strong preclinical evidence of activity Phase IA: Safety Phase I-II Dose-response Randomised Comparison Biological endopint Stop if no activity – Unselected pts Phase IIB Surrogate endpoint (sel. Pts) Stop if no difference with control arm (futility) or toxicity Efficacy (OS, PFS, RFS) Stop random if suff. evid. of efficacy

110 Development of targeted therapies Bayesian Statistics 1.To monitor study results for early stop 2.To use validated surrogate endpoints 3.To extrapolate results across cancers of different sites bearing the same target

111 A therapy targeted at a specific mutation in gene X has been demonstrated in RCT’s to improve survival in resected pts with the mutation (20%), (lung c., colon c., prostate c. and breast c.), with reductions in mortality of 20-40%

112 A therapy targeted at a specific mutation in gene X has been demonstrated in RCT’s to improve survival in resected pts with the mutation (10%), (lung c., colon c., prostate c. and breast c.), with reductions in mortality of 20-40% We want to show its efficacy (phase III trial) in osteosarcomas with the same mutation

113 A therapy targeted at a specific mutation in gene X has been demonstrated in RCT’s to improve survival in reseted pts with the mutation (10%), (lung c., colon c., prostate c. and breast c.), with reductions in mortality of 20-40% We want to show its efficacy (phase III trial) in osteosarcomas with the same mutation Null Hypothesis? - Evidence needed to accept the efficacy of the new treatment in osteosarcomas?

114 Test of significance? Mortality Other Tumors Nil vs B 15% vs 12.5% N=12000 P = Osteosarcoma Nil vs B 15% vs 8.3% N= 240 P = 0.11

115 Summary The assessment of the activity of a treatment is critical in its development The methodology of trials derives from the therapeutic paradygm A priority of modern cancer research is the identification of efficient (sensitive and specific) markers of activity for phase II trials of novel drugs

116 Conclusions Development of cytotoxic drugs –Fixed Standard Methodologies –Roles: Phase I - Pharmacologist Phase II – Oncologist (+Statistician/Simon‘s tables) Phase III – Oncologist + Statistician (sample size and analysis)

117 Conclusions Development of novel drugs –Specific (original) methodology developed, monitored and re-adjusted for each new drug –Roles: Multidisciplinary teams (Basic Researcher+Oncologist+Statistician) working together in the design, conduct and interpretation of all phases of development

118 Traditional Role of the Statistician

119 Tell me, Paolo, how many patients do I need for…..?

120 ..back to the PC….and…

121 …for alfa= and power % you need 806,913.8 patients!

122 New duties of the statistician Learn about biology!

123 New duties of the statistician Think!

124 Listen, propose and discuss! New duties of the statistician

125 Think again!

126 Until you find a rational solution


Download ppt "Clinical trials challenges with targeted agents Paolo Bruzzi Clinical Epidemiology, Dept. of Epidemiology and Prevention, Istituto Nazionale per la Ricerca."

Similar presentations


Ads by Google