Introduction

We analysed, in a previous application note, the interest of using a functional complementary diagnostic (CoDx), the Oncogramme, to improve the selection of patients in phase III clinical studies for new drugs in oncology¹. This previous study was based on data from the literature indicating that¹:

• Clinical study success rate (from phase I to approval) for a new drug in oncology is less than 4%².
• 62% of phase III clinical studies in oncology did not achieve result with statistical significance².
• The major reason of clinical trial failure is a lack of clinical efficacy (40%-50%)³.
• Select treated population in phase III clinical studies in oncology, by a biomarker approach, multiply by 2 the success rate².

 

Based on these data, we explained the advantage of using Oncogramme, a standardized functional assay, allowing the quantitative evaluation of the anti-cancer capacities of a molecule directly on primary cancer cells (2D culture) extracted from a patient's tumour; with a more than 80% of predictivity, to improve the selection of patients treated by a new drug in phase III clinical trials in Oncology ^1,4–8.

Linked to the multiplication of ways to treat cancer diseases (chemotherapy, hormonotherapy, radiotherapy, immunotherapy, laser treatment, targeted therapy,…) several studies have reported the improved results of combination of two or more compounds compared to the use of single drugs⁹. Recent studies discussed about difficulties to evaluate cancer treatments synergistic effects, due to the absence of standard reference model to evaluate synergies ⁹.

In this new application note, we discuss the interest of using the Oncogramme to improve selection of patient as part of synergistic studies in phase III clinical studies in oncology.

1. Synergistic clinical trial

During previous decades, we observed an evolution in cancer treatment from relatively non-specific cytotoxic agents, to selective and mechanisme-based therapeutics. Initially, chemotherapies against cancer were identified for their abilities to kill rapidly dividing cells. These drugs, although limited by their toxicities and frequently acquired resistances, remain the most prescribed treatment against cancer. Last years, linked to the improvement of cancer pathogenesis knowledge, new treatments, like targeted agents and cancer immunotherapy, arrived¹⁰.

The current cancer treatments includes a variety of strategies, with a unique treatment, or a combination of two or more types of treatment, determined by a wide range of criteria like type of cancer, stage of the tumour and patient characteristics¹¹.

National cancer institute lists the types of cancer treatment as follows¹¹:

• Chemotherapy
• Hormone therapy
• Hyperthermia
• Immunotherapy
• Photodynamic therapy
• Radiation Therapy
• Stem cell transplant
• Surgery
• Targeted therapy

If a treatment by a unique drug may be sufficient, recent studies have reported the improved results of combinations of two or more compounds compared to the use of single drugs¹⁰. In addition, treatment combinations are currently used in certain therapeutic approaches. Many advanced solid cancers are now treated with multidrug combinations (in addition to surgery and radiation where applicable)¹². For example, we can find the drug combinations used in Colon Cancer treatment¹³ on the NIH website .

We can classify the combinations of treatments against colorectal cancer as follows:

► Chemotherapy combinations: CAPOX, FOLFIRI, FOLFOX, FU-LV, XELIRI, XELOX

► Chemotherapies + anti-VEGF Primary antibody combination: Folfiri-Bevecizumab (Folinic Acid + Fluorouracil + Irinotecan Hydrochloride + Bevacizumab), so three chemotherapies and one anti-VEGF primary antibody.

► Chemotherapies + anti-EGFR Primary antibody combination: Folfiri-Cetuximab: (Folinic Acid + Fluorouracil + Irinotecan Hydrochloride + Cetuximab), so three chemotherapies and one anti-EGFR primary antibody.

These three types of combinations illustrate the difficulties to create and analyse clinical trials to study synergistic effects. Indeed, it’s not possible to use the same methodology to analyse:

• A combination of drugs (chemotherapies and/or antibodies) where all the drugs have a direct toxic effect on cancer cells
• A combination of drugs (chemotherapies and/or antibodies) where only few drugs have a direct toxic effect in cancer cells and others in cancer micro-environment (angiogenesis) or module immune-system
• A combination of drugs (chemotherapies and/or antibodies) where only few drugs have a direct toxic effect on cancer cells and others have a complex effect, like direct effect in cancer cells + micro-environment effect (anti-EGFR for example) and/or + immune-system modulation (anti-PD-L1 for example)

For this application note, we chose to describe how Oncogramme can help for synergistic studies during phase III clinical trial in oncology using two examples:

• With a combination of drugs (chemotherapies and/or antibodies) where all the drugs have a direct toxic effect on cancer cells
• With combination of drugs (chemotherapies and/or antibodies) where only few drugs have a direct toxic effect on cancer cells and others on the cancer micro-environment (angiogenesis) or modulate the immune-system

2. The Oncogramme^®, Complementary diagnostic Functional Assay platform for clinical studies

The Oncogramme^® is a functional assay that consists in the measurement of therapy-induced mortality on patient primary 2D cancer cultures cells, using fluorescence microscopy. This test is fully standardized, allowing both reliability and a high success rate.

The Oncogramme^® is a standardized technological platform, based on 3 pillars:

First, a standardized tumor treatment procedure that has been correlated with clinical data.

Second, a kit of culture media and proprietary reagents for sending the sample, dissociation and specific culture of primary cancer cells.

And finally, a proprietary algorithm for automatic counting correlated with clinical data^4–8.

These three Oncogramme^® pillars make it possible to obtain more than 80% of predictivity⁴. This technological platform has been developed by Oncomedics for CRC, breast, ovarian, glioblastoma, lung, and is ready for new cancer localisation development.

The Oncogramme^® technical protocol (Fig. 1) takes place in less than 15 days. This procedure begins on day 1 by the biopsy or the excision of the tumor by a surgeon. The excised tumor is sent to the pathology laboratory, which separates the tumor into several parts, one of which is dedicated to the Oncogramme^®. The tumor part is placed in a conservation medium with a proprietary formulation, which preserves the viability of the cells for 48 hours at 4°C, i.e. the time necessary for the shipment of the sample from the hospital to the laboratory. Once in the laboratory, the tumor is dissociated using a proprietary medium, which allows dissociation with high cell viability (>80%) and preservation from contamination in more than 95% of cases. Subsequently, the tumor cells obtained are cultured in another proprietary medium, allowing the purification of the cell population and its enrichment. After culture, patient cancer cells are brought into contact with the different chemotherapies, and the induced cell death is analysed by a double fluorescence staining system. This is followed by the drafting of a report presenting the standardized response profile of the patient's tumor. The practitioner can then choose the treatment identified as the most effective in the patient’s cancer cells with 84% predictivity.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Figure 1: Overview of the Oncogramme^® experimental procedure, from surgery to readout. Viable samples were recovered and processed to obtain primary cultures that were subsequently utilized for realization of the Oncogramme^® by exposure to chemotherapeutic drugs and cell death analysis. Whole time course was less than 2 weeks

Results of the Oncogramme^® is a diagram showing quantitative sensitivity or resistance rate of the patient tumor to the different chemotherapies. On  Fig. 2, we can observe as an example for metastatic colorectal cancer Oncogramme (CE-IVD), the results of a tumor that is non sentitive to 5FU + Folic acid and sensitive to Folfirinox, Folfox and Folfiri. Maximum tumor sensitivity is observed with Folirinox.

The crucial point for CRCm Oncogramme^®(CE-IVD) is, that using this functional test makes it possible to go from less than 50% chance of response to the first line chemotherapy¹⁴ to 84% of chance⁴. So, without Oncogramme^®, the patient has one chance out of two to receive an effective chemotherapy in first line¹⁴. With a treatment that, in accordance with the Oncogramme®, increases the cell death of the patient's cancer cells, the patient has a 84% chance of actually having their tumour targeted⁴.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Figure 2: Example of Oncogramme^® for metastatic colorectal cancer (CE-IVD) graphic results

 

3. How can Oncogramme^® secure synergistic studies during phase III clinical studies in Oncology?

 

In Oncology, phase III of a clinical study is a crucial step in drug development process, because it represents the most costly step and takes a long time before obtaining the results. Additionally, phase III compares a new treatment with the standard of care. Regarding this specific point, literature highlighted how it’s difficult to identify, for a new drug, a statistic difference versus standard of care¹⁴. As an example, a study on 1245 clinical trials in oncology between January 1, 2000 to October 31, 2015 highlights only 35.5% (SE 1.4%) success rate from phase III to approval. The use of a biomarker can improve the rate of positive phase III trials from 33.6% (SE 1.4%) without a biomarker and approach to 63.6% (SE 5.5%) with a biomarker². However, even with a biomarker, almost 40% of phase III clinical studies fail, half of them due to a lack of efficacy¹⁴.

We have previously published how high predictivity of CSRA functional assays can improve the success rate of clinical trials in oncology¹. To go further, we explain how the high predictivity of Oncogramme^® technological platform can help pharma and biotech companies to secure synergistic studies during phase III clinical trial in oncology using two examples:

• With a combination of drugs (chemotherapies and/or antibodies) where all the drugs have a direct toxic effect on cancer cells (Fig. 3).
• With a combination of drugs (chemotherapies and/or antibodies) where only few drugs have a direct toxic effect on cancer cells and others in cancer micro-environment (angiogenesis) or module immune-system (Fig. 4).

 

A) Drug Combination 1: All the drugs in the combination have a direct cancer cell toxic effect

 

This clinical trial studies the effect of a new drug, described with a direct toxic effect in tumor cells during preclinical studies, and its potential synergistic effect with two standard of care chemotherapies (Folfox and Folfiri) in CRCm randomized patients.

In a classical phase III synergistic oncology clinical study for a new anti-CRCm drug (Fig. 3A), randomized patients are separated into two arms. First arm with half of the randomized patients, treated with the new drug and standard of care (Folfox or Folfiri). The second one, with the other half of the patients, treated by standard of care only (Folfox or Foliri). If we decide to add 300 randomized patients in the clinical study, 150 patients receive standard of care (Folfox or Folfiri). As previously published, with Folox or Folfiri we will observe a first line patient answer in less than 50% of cases¹⁴. So, on 150 Folfox or Folfiri treated patients, NR (number of patients responding to drug) might be 75. For new drug + Folfox or Folfiri, we test 150 patients too. To obtain a clinical trial success, the new drug + standard of care must have more than 50% of positive answer. So, there are high risks to not obtain statistical difference between the new drug + standard of care results and the standard of care only results, thus a clinical study failure.

Our proposition, to improve the success rate of this clinical trial, is adding an Oncogramme^® in the new drug arm, before treating patients with the new drug + Folfox or Folfiri (Fig. 3B). We choose to create a study with 300 randomized patients, 100 patients on standard of care arm, 200 patients on new drug arm. In this new clinical study, the standard of care arm, with Folfox and Folfiri, stays at less than 50% of responding patients¹⁴. If we treat 100 patients, about 48 might have a real drug effect. For the new drug + standard of care arm, we can perform new drug + Folfox or Folfiri determined by Oncogramme^® on 200 randomized patients. This first step will drop-out all the patients not-responding to the new drug + standard of care, with a predictivity of 84%⁴. If the effectiveness of the new drug + standard of care combination is something like 50%, half of the 200 randomized patients, identified as new drug + Folfox or Folfiri non sensitive tumors determined by the Oncogramme^®, will be droped-out. For this example, we choose to drop-out 104 patients not-responding to the new drug + standard of care. So, only the patients identified with a sensitive tumor using Oncogramme^®, 96 patients in this example,  will receive the treatment with the new drug + standard of care. As the predictivity of the Oncogramme^® on metastatic colorectal cancer is 84%, we will observe a real effect of the new drug + standard of care on 84% of treated patients. Thus, about 72 responding patients in 96 treated patients. In this case, we can identify a real statistical difference compared to the standard of care (less than 50% of responding patients for standard of care vs 84% of responding patients for New Drug).

This example illustrates that Oncogramme^® drastically improves the chance of success in synergistic phase III clinical study by selecting the new drug + standard of care responding tumors and secures the Phase III clinical trial, if all the drugs have a direct toxic effect on cancer cells.

Another major advantage: using the Oncogramme^® drastically decreases the number of patients not-responding to the new drug + standard of care combination that receive the new drug + Folfox or Folfiri without any effect against their tumor, but with side effects of the new drug.

In the classical study, 50% of the patients treated by the new drug receive the new drug without anti-tumor effect. Using the Oncogramme^®, only 16% of the patients treated by the new drug receive the new drug without anti-tumor effect.

 

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Figure 3A: Classical synergistic study phase III clinical trial for new anti-CRC drug with a direct toxicity effect on cancer cells in combination with classical chemotherapy (Folfox or Folfiri).

 

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Figure 3B: Synergistic study phase III clinical trial for new anti-CRC drug with a direct toxicity effect on cancer cells in combination with classical chemotherapy (Folfox or Folfiri) including patient selection using the CRC Oncogramme^®.

 

B) Drug Combination 2: Only some drugs in the combination have a direct toxic effect on cancer cells

 

This clinical trial studies the effect of a new drug, described with no direct toxic effect on tumour cells during preclinical studies, and its potential synergistic effect with two standard of care chemotherapies (Folfox and Folfiri) in CRCm randomized patients. This new drug can, for example has an effect in tumour micro-environment (anti-VEGF for example) or as an immunomodulator.

In a classical phase III synergistic oncology clinical study for a new anti-CRCm drug (Fig4A), randomized patients are separated in two arms.

First arm with half of the randomized patients, treated with the new drug and standard of care (Folfox or Folfiri).

The second one, with the other half of the patients, treated by standard of care only (Folfox or Foliri). If we decide to add 300 randomized patients in the clinical study, 150 patients receive standard of care (Folfox or Folfiri).

As previously published, with Folox or Folfiri we will observe a first line patient answer in less than 50% of cases¹⁴. So, on 150 Folfox or Folfiri treated patients, NR (number of patients responding to the drug) might be 75. For new drug + Folfox or Folfiri, we test 150 patients too. To obtain a clinical trial success, the new drug + standard of care must have more than 50% of positive answer. So, there is a high risks to not obtain statistical difference between the new drug + standard of care results and the standard of care only results, so a clinical study failure.

Our proposition, to improve the success rate of this clinical trial, is adding the Oncogramme^® in the new drug + standard of care arm, before treating patients with the new drug + Folfox or Folfiri (Fig4B). As the new drug has no direct toxic effect on tumour cells, it’s not possible to include it in an Oncogramme^®. We choose to create a study with 300 randomized patients, 100 patients on the standard of care arm, 200 patients on the new drug arm. In this new clinical study, the standard of care arm, with Folfox and Folfiri, stays at less than 50% of responding patients¹⁴. If we treat 100 patients, about 48 might have a real drug effect. For the new drug + standard of care arm, we can perform Folfox or Folfiri Oncogramme on 200 randomized patients. This first step will drop-out all the patients not-responding to the standard of care, with a predictivity of 84%⁴. As effectiveness of Folfox and Folfiri is less than 50%¹⁴, one half of the 200 randomized patients, identified as Folfox or Folfiri non sensitive tumors using the Oncogramme^®, will be droped-out. For this example, we choose to drop-out 104 patients non-responding to standard of care. So, only the patients identified with a Folfox or Folfiri sensitive tumor using the Oncogramme^®, 96 patients in this example,  will receive the treatment with the new drug + standard of care. As the predictivity of the Oncogramme^® on metastatic colorectal cancer is 84%, we will observe a real effect of Folfox or Folfiri in 84% of standard of care + new drug treated patients. So, as the Oncogramme^® selected the patients responding to standard of care, it will be easy to study the real synergistic effect of the new drug with standard of care.

This example illustrates that Oncogramme^® drastically improves the chances of success in synergistic phase III clinical study by selecting the standard of care responding tumors and secures the phase III clinical trial if only part of the drugs have a direct toxic effect on cancer cells.

The other major advantage is that using Oncogramme drastically decreases the number of patients non-responding to the standard of care combination that receive the new drug + Folfox or Folfiri without any effect of standard of care against their tumor, but with side effects.

 

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Figure 4A: Classical synergistic study phase III clinical trial for new anti-CRC drug without direct toxicity effect on cancer cells in combination with classical chemotherapy (Folfox or Folfiri).

 

 

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Figure 4B: Synergistic study phase III clinical trial for new anti-CRC drug without direct toxicity effect on cancer cells in combination with classical chemotherapy (Folfox or Folfiri) including patient selection using CRC Oncogramme^®.

 

Discussion

 

An oncology clinical trial is a long and costly process with a high rate of failure³. Since years, the biomarker strategy, via Cdx, tried to decrease the high rate of clinical failures, linked to a lack of clinical efficacy (40%–50% of the clinical trial failure)³. This approach, specifically for phase III of oncology clinical trials, increased the success rate from 33,6% without biomarker to 63,6% with biomarkers². However, the phase III failure rate stays high.

In this application note, we are proposing a new approach to improve the oncology synergistic clinical trial success rate:

Using a CoDx CSRA functional assay to improve the patient selection during phase III of clinical trials in oncology. 

 

The high predictivity (more than 80%)¹⁵ of CSRA functional assays make it possible to:

• Secure and increase success rate of synergistic phase III clinical study in oncology by selecting with a more than 80% predictivity, the patients responding to a drug with a direct anti-tumor effect.
• Decrease the number of patients, included in a phase III clinical trial in oncology, that receive a  drug as treatment without any anti-tumour effect on their tumor cells.
• Increase the value of the new anti-tumor drug with an associated CoDx
• Work on drug repositioning by identifying new responding populations

We are convinced that the Oncogramme^® technology platform is the best CSRA candidate for your phase III clinical study in oncology because :

•  The Oncogramme® is a standardized and easy to develop technology platform validated by clinical data.
•  High predictivity of the Oncogramme^® results (more than 84% of predictivity)⁴
• The Oncogramme^® can predict anti-tumor activity not only for chemotherapies but for all drugs with a direct effect on tumor cells (immunotherapy, ADC,…)
• The Oncogramme^® can predict synergic effect like Chemotherapy + Chemotherapy, or Chemotherapy + Immunotherapy by selecting patients responding to a drug with a direct anti-tumor effect.
• Ready for IVD functional assay: Colorectal cancer (IVD); Breast and Ovarian (ready for IVD) ; Lung, Glioblastoma, Prostate,… (In progress)
• Long experience of working with biotech and pharma companies
• Research and development performed internally at Oncomedics’ laboratories. The Oncogramme^® test can be performed by a major European clinical diagnostic laboratory.

 

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